[ CAS No. 110661-91-1 ] {[proInfo.proName]}

Name: 110661-91-1|tert-Butyl 4-bromobutanoate|97%
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Quality Control of [ 110661-91-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 110661-91-1 ]

Product Details of [ 110661-91-1 ]

CAS No. :	110661-91-1	MDL No. :	MFCD02179416
Formula :	C₈H₁₅BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HJEZRYIJNHAIGY-UHFFFAOYSA-N
M.W :	223.11	Pubchem ID :	2757253
Synonyms :

Calculated chemistry of [ 110661-91-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.88
Num. rotatable bonds :	5
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.76
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.13 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.71
Log Po/w (XLOGP3) :	2.15
Log Po/w (WLOGP) :	2.5
Log Po/w (MLOGP) :	2.43
Log Po/w (SILICOS-IT) :	2.23
Consensus Log Po/w :	2.4

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.25
Solubility :	1.26 mg/ml ; 0.00565 mol/l
Class :	Soluble
Log S (Ali) :	-2.33
Solubility :	1.03 mg/ml ; 0.00463 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.85
Solubility :	0.312 mg/ml ; 0.0014 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.11

Safety of [ 110661-91-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 110661-91-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 110661-91-1 ]
Downstream synthetic route of [ 110661-91-1 ]

[ 110661-91-1 ] Synthesis Path-Upstream 1~5

1
[ 2623-87-2 ]
[ 75-65-0 ]
[ 110661-91-1 ]

Yield	Reaction Conditions	Operation in experiment
47%	With sulfuric acid; magnesium sulfate In dichloromethane at 20℃; for 48 h;	Compound 31 was synthesized in accordance with the following scheme. 4-bromo-butyric acid (2.57 g, 15.39 mmol, 1 eq.) was dissolved in dichloromethane (20 ml), magnesium sulfate (7.74 g, 64.30 mmol, 4.2 eq.), tert-butyl alcohol (5.70 g, 76.95 mmol, 5 eq.), and concentrated sulfuric acid (0.25 mE) were added, and the mixture was stirred for 2 days at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added and extracted using dichloromethane, the organic layer was then washed using a saturated sodium chloride solution and dried using anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by medium-pressure silica gel chromatography (eluent:n-hexane/ethyl acetate=50/50) to obtain the objective compound 31(1.17 g, 5.24 mmol, 47percent). 1H NMR (400 MHz, CDCl3): δ 1.27 (s, 9H),1.91-1.98 (m, 2H), 2.22 (t, 2H, J=7.2 Hz), 3.27 (t, 2H, J=6.5Hz); 13C NMR (100 MHz, CDCl3): δ 27.9, 28.0, 32.8, 33.7,80.5, 171.7.

Reference： [1] Tetrahedron Asymmetry, 2004, vol. 15, # 8, p. 1247 - 1258
[2] ACS Combinatorial Science, 2016, vol. 18, # 12, p. 710 - 722
[3] Angewandte Chemie - International Edition, 2010, vol. 49, # 15, p. 2738 - 2742
[4] European Journal of Organic Chemistry, 2003, # 8, p. 1486 - 1493
[5] Patent: US2018/52109, 2018, A1, . Location in patent: Paragraph 0156; 0157; 0158; 0159
[6] Advanced Synthesis and Catalysis, 2007, vol. 349, # 3, p. 432 - 440
[7] Synthesis, 2010, # 24, p. 4261 - 4267
[8] Tetrahedron, 1992, vol. 48, # 42, p. 9277 - 9282
[9] Patent: WO2004/65491, 2004, A1, . Location in patent: Page 22

2
[ 2623-87-2 ]
[ 115-11-7 ]
[ 110661-91-1 ]

Yield	Reaction Conditions	Operation in experiment
32%	With sulfuric acid In dichloromethane at -78 - 20℃; for 72 h;	4-Bromobutanoic acid (9.76 g, 58.4 mmol) and concentrated H₂SO₄ (3 drops) were dissolved in CH₂Cl₂ (20 mL) and the mixture was cooled to -78 °C. Isobutylene was bubbled into the solution until the volume doubled. The reaction mixture was stirred for 3 days at room temperature before it was cooled to -78 °C and N₂ was bubbled into the reaction mixture to remove excess isobutylene. The reaction mixture was diluted with CH₂Cl₂ and washed with aqueous 2 N KOH and saturated aqueous NaCl, and concentrated to yield tert-buty\\ 4-bromobutanoate (4.13 g, 32percent) which required no further purification.

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 14, p. 3359 - 3368
[2] Patent: WO2008/150492, 2008, A1, . Location in patent: Page/Page column 81

3
[ 59854-12-5 ]
[ 110661-91-1 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 4, p. 958 - 963

4
[ 2623-87-2 ]
[ 115-11-7 ]
[ 65868-63-5 ]
[ 110661-91-1 ]

Reference： [1] Patent: US2002/68722, 2002, A1,

5
[ 110661-91-1 ]
[ 102971-73-3 ]

Reference： [1] Collection of Czechoslovak Chemical Communications, 1992, vol. 57, # 6, p. 1335 - 1344

[ 110661-91-1 ] Synthesis Path-Downstream 1~88

1
[ 2623-87-2 ]
[ 75-65-0 ]
[ 110661-91-1 ]

Yield	Reaction Conditions	Operation in experiment
95%		Combine 4-bromobutyric acid (3.0g, 16.57mmol, 1.0eq) with 20mL of anhydrous tetrahydrofuran, cool to -40 C, and add trifluoroacetic anhydride (6.96g, 33.14mmol, 2.0eq) dropwise After stirring at -40 C for 30 minutes, tert-butanol (9.83g, 132.56mmol, 8.0eq) was gradually added to room temperature and reacted overnight.After the reaction was completed, the reaction system was poured into a saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride, and concentrated under reduced pressure to obtain 3.75 g of a light yellow oil with a yield of 95%.
47%	With sulfuric acid; magnesium sulfate; In dichloromethane; at 20℃; for 48h;	Compound 31 was synthesized in accordance with the following scheme. 4-bromo-butyric acid (2.57 g, 15.39 mmol, 1 eq.) was dissolved in dichloromethane (20 ml), magnesium sulfate (7.74 g, 64.30 mmol, 4.2 eq.), tert-butyl alcohol (5.70 g, 76.95 mmol, 5 eq.), and concentrated sulfuric acid (0.25 mE) were added, and the mixture was stirred for 2 days at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added and extracted using dichloromethane, the organic layer was then washed using a saturated sodium chloride solution and dried using anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by medium-pressure silica gel chromatography (eluent:n-hexane/ethyl acetate=50/50) to obtain the objective compound 31(1.17 g, 5.24 mmol, 47%). 1H NMR (400 MHz, CDCl3): delta 1.27 (s, 9H),1.91-1.98 (m, 2H), 2.22 (t, 2H, J=7.2 Hz), 3.27 (t, 2H, J=6.5Hz); 13C NMR (100 MHz, CDCl3): delta 27.9, 28.0, 32.8, 33.7,80.5, 171.7.
		50 g (0.30 mol) of 4-bromobutyric acid is mixed drop by drop in 400 ml OF THF AT-40C with 187 g (0.89 mol) of trifluoroacetic acid anhydride. After 30 minutes of stirring AT-40C, 400 ml of tert-butanol/30 ml of THF is added in drops within 1 hour. After 16 hours of stirring at room temperature, the reaction mixture is poured onto an ice-cooled sodium carbonate solu- tion, the aqueous phase is extracted three times with diethyl ether, and the organic phases are dried on sodium sulfate and concentrated by evaporation. The residue is distilled in a vacuum (boiling point 72C/0. 9 mbar; yield: 41 g). The reaction to form phosphonium salt is carried out by reflux-heating 41 g (0.18 mol) of intermediate product, 44.6 g (0.17 mol) of triphenyl- phosphine and 32.5 g (0.36 mol) of sodium bicarbonate in 250 ml of acetonitrile for 20 hours. The reaction mixture is filtered, concentrated by evaporation, and the residue is brought to crystallization by stirring with diethyl ether. Yield: 58.5 g (40% of theory, relative to 4- bromobutyric acid) of a white solid.

Reference： [1]Patent: CN110963994,2020,A .Location in patent: Paragraph 0475; 0977-0980
[2]Tetrahedron Asymmetry,2004,vol. 15,p. 1247 - 1258
[3]ACS Combinatorial Science,2016,vol. 18,p. 710 - 722
[4]Angewandte Chemie - International Edition,2010,vol. 49,p. 2738 - 2742
[5]European Journal of Organic Chemistry,2003,p. 1486 - 1493
[6]Patent: US2018/52109,2018,A1 .Location in patent: Paragraph 0156; 0157; 0158; 0159
[7]Advanced Synthesis and Catalysis,2007,vol. 349,p. 432 - 440
[8]Synthesis,2010,p. 4261 - 4267
[9]Tetrahedron,1992,vol. 48,p. 9277 - 9282
[10]Patent: WO2004/65491,2004,A1 .Location in patent: Page 22
[11]Journal of Medicinal Chemistry,2019,vol. 62,p. 1420 - 1442

2
[ 25518-33-6 ]
[ 110661-91-1 ]
[ 437753-99-6 ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 5673 - 5683

3
[ 1006-39-9 ]
[ 110661-91-1 ]
4-(2-acetyl-5-fluorophenyl)butyric acid tert-butyl ester [ No CAS ]

Reference： [1]Tetrahedron Asymmetry,2004,vol. 15,p. 1247 - 1258

4
[ 52959-28-1 ]
[ 110661-91-1 ]
[ 874210-33-0 ]

Yield	Reaction Conditions	Operation in experiment
85.1%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide for 48h; Heating;

Reference： [1]Yuan, Lihua; Sanford, Adam R.; Feng, Wen; Zhang, Aimin; Zhu, Jin; Zeng, Huaqiang; Yamato, Kazuhiro; Li, Minfeng; Ferguson, Joseph S.; Gong, Bing [Journal of Organic Chemistry, 2005, vol. 70, # 26, p. 10660 - 10669]

5
[ 271261-71-3 ]
[ 110661-91-1 ]
[ 874210-16-9 ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 10660 - 10669

6
[ 13314-85-7 ]
[ 110661-91-1 ]
[ 697753-62-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 1737 - 1749

7
[ 5586-73-2 ]
[ 110661-91-1 ]
[ 1002566-64-4 ]

Yield	Reaction Conditions	Operation in experiment
52.6%	With potassium carbonate; In acetonitrile;Heating / reflux;	EXAMPLE 67 (R)-l-(3<3-diphenvIpropyI)-3-(4-(4-(methylsuIfonamido)phenyl)thiazol-2-vI)-l-(4-oxo-4-(piperidin-3-ylamino)butvI)urea; Step 1: Tert-butyl 3-bromopropionate 1 (0.5 mL, 3.0 mmol) was dissolved in 100 mL of dry acetonitrile. To this solution was added potassium carbonate (0.415g, 3.0 mmol) and 3,3-diphenylpropylamine 2. The reaction mixture was refluxed overnight. The mixture was then allowed to cool to room temperature and was concentrated in vacuo. The crude residue obtained was dissolved in ethyl acetate (45 mL) and washed with saturated aqueous ammonium chloride solution and then with brine. The organics were dried over magnesium sulfate, filtered and concentrated to obtain the crude product as a clear oil. This product was purified by column chromatography on silica using 89:9:l/DCM:MeOH:ammonium hydroxide as eluent. Fractions containing product were combined and concentrated in vacuo to obtain 3 as a white solid (0.54g, 52.6% yield).

Reference： [1]Patent: WO2008/6625,2008,A2 .Location in patent: Page/Page column 65

8
[ 2623-87-2 ]
[ 115-11-7 ]
[ 110661-91-1 ]

Yield	Reaction Conditions	Operation in experiment
32%	With sulfuric acid; In dichloromethane; at -78 - 20℃; for 72h;	4-Bromobutanoic acid (9.76 g, 58.4 mmol) and concentrated H2SO4 (3 drops) were dissolved in CH2Cl2 (20 mL) and the mixture was cooled to -78 C. Isobutylene was bubbled into the solution until the volume doubled. The reaction mixture was stirred for 3 days at room temperature before it was cooled to -78 C and N2 was bubbled into the reaction mixture to remove excess isobutylene. The reaction mixture was diluted with CH2Cl2 and washed with aqueous 2 N KOH and saturated aqueous NaCl, and concentrated to yield tert-buty 4-bromobutanoate (4.13 g, 32%) which required no further purification.

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3359 - 3368
[2]Patent: WO2008/150492,2008,A1 .Location in patent: Page/Page column 81

9
[ 110661-91-1 ]
[ 6182-78-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium iodide; In acetone; for 3h;Heating / reflux;	tert-Butyl 4-bromobutanoate (2.29 g, 10.2 mmol) was dissolved in acetone (40 mL) and NaI (3.08 g, 20.5 mmol) was added. The reaction mixture was warmed to reflux for 3 h under an Ar atmosphere. The acetone was removed in vacuo and the resulting residue was dissolved in EtOAc. The solution was washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated to yield tert-bxlambday 4- iodobutanoate (2.29 g, 83%) which required no further purification.

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3359 - 3368
[2]Patent: WO2008/150492,2008,A1 .Location in patent: Page/Page column 81

10
[ 110661-91-1 ]
[ 102971-73-3 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1992,vol. 57,p. 1335 - 1344

11
[ 110661-91-1 ]
[ 603-35-0 ]
[ 731862-95-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium hydrogencarbonate; In acetonitrile; at 85℃;	A flask was charged with tert-butyl 4-bromobutanoate (500 mg, 2.24 mmol, 1.00 equiv), MeCN (15 mL), triphenylphosphine (590 mg, 2.25 mmol, 1.00 equiv), and sodium bicarbonate (378 mg, 4.50 mmol, 2.00 equiv). The resulting solution was stirred overnight at 85 C. and cooled to rt. The mixture was filtered and the filtrate was concentrated. The residue was triturated with diethyl ether to provide 650 mg (60% yield) of (4-(tert-butoxy)-4-oxobutyl)triphenylphosphonium bromide as a white solid. LCMS (ESI, m/z): 405 [M-Br]+.
	With sodium hydrogencarbonate; In acetonitrile; for 20h;Heating / reflux;	50 g (0.30 mol) of 4-bromobutyric acid is mixed drop by drop in 400 ml OF THF AT-40C with 187 g (0.89 mol) of trifluoroacetic acid anhydride. After 30 minutes of stirring AT-40C, 400 ml of tert-butanol/30 ml of THF is added in drops within 1 hour. After 16 hours of stirring at room temperature, the reaction mixture is poured onto an ice-cooled sodium carbonate solu- tion, the aqueous phase is extracted three times with diethyl ether, and the organic phases are dried on sodium sulfate and concentrated by evaporation. The residue is distilled in a vacuum (boiling point 72C/0. 9 mbar; yield: 41 g). The reaction to form phosphonium salt is carried out by reflux-heating 41 g (0.18 mol) of intermediate product, 44.6 g (0.17 mol) of triphenyl- phosphine and 32.5 g (0.36 mol) of sodium bicarbonate in 250 ml of acetonitrile for 20 hours. The reaction mixture is filtered, concentrated by evaporation, and the residue is brought to crystallization by stirring with diethyl ether. Yield: 58.5 g (40% of theory, relative to 4- bromobutyric acid) of a white solid.

Reference： [1]Patent: US2018/134674,2018,A1 .Location in patent: Paragraph 0412; 0413
[2]Patent: WO2004/65491,2004,A1 .Location in patent: Page 22

12
[ 110661-91-1 ]
[ 154598-52-4 ]
4-(6-chloro-4-cyclopropylethynyl-2-oxo-4-trifluoromethyl-4H-benzo[d][1,3]oxazin-1-yl)-butyric acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With monopotassium carbonate; 18-crown-6 ether; sodium iodide; In DMF (N,N-dimethyl-formamide); at 125℃; for 2h;	To 250 mg (0.79 mmol) of efavirenz 1 was added 10 mL of anhydrous DMF, 600 mg (4.34 mmol) of potassium carbonate, 120 mg (0.80 mmol) of sodium iodide and 492 mg (2.2 mmol) of 4-bromo-butyric acid tert-butyl ester followed by 5 mg of 18-crown-6. The mixture was heated to 125 C for 2 hours under argon atmosphere and concentrated under reduced pressure. To the residue 50 mL of chloroform was added, and the solid was filtered off. To the filtrate 50 mL of water was added. The organic layer was separated, washed with 50 mL of water, dried (Na2SO4), and concentrated. The residue was purified by silica gel flash column chromatography in 70% ethyl acetate in hexane to give 327 mg (0.721 mmol, 90% yield) of 2.

Reference： [1]Patent: EP1470825,2004,A1 .Location in patent: Page/Page column 6-7

13
[ 842167-75-3 ]
[ 110661-91-1 ]
4-(3,5-dichloro-pyridin-4-yl-methyl)-7-methoxy-2-[tert-butoxycarbonyl-(3-tert-butoxycarbonyl-propyl)-amino-sulfonyl]-1,2-dihydro-phthalazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With TBD-methyl polystyrene; In DMF (N,N-dimethyl-formamide); dichloromethane; at 35℃; for 15h;	A mixture of compound 4 (500 mg, 1 mmoles), 4-bromo-butyrate of ter-butyl (268 mg, 1.2 mmoles) and TBD-methyl polystyrene (500 mg, 1.4 mmoles) in DCM/DMF 1: 3 (12 ml) is stirred at 35C for 15 hours. The resin is filtered and washed with DCM (2 x 4 ml) and DMF (5 ml), then the solvent is evaporated and the crude is purified on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MEOH 95: 5. The compound 43 as white solid is obtained (483 mg, yield: 75%). Rt: 4.25 min. [M+H] + 645

Reference： [1]Patent: WO2005/13995,2005,A1 .Location in patent: Page/Page column 34

14
[ 381213-44-1 ]
[ 110661-91-1 ]
1α,3β-dihydroxy-20(S)-tert-butoxycarbonylpropylthio-9,10-secopregna-5,7,10(19),16-tetraene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With sodium hydroxide; In water; at 20℃; for 0.5h;	Example 87 Preparation of 1alpha,3beta-dihydroxy-20(S)-tert-butoxycarbonylpropylthio-9,10-secopregna-5,7,10(19),16-tetraene 1alpha,3beta-Dihydroxy-20(S)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene (6.2 mg, 0.0133 mmol) was treated with a 2M aqueous sodium hydroxide (65 mul) and <strong>[110661-91-1]tert-butyl 4-bromobutyrate</strong> (155.0 mg, 0.695 mmol) in the same manner as shown in Example 16(2) (at room temperature for 30 minutes) and then worked up. The resulting residue was purified by preparative thin layer chromatography (0.25 mm1 plate, dichloromethane:ethanol=20:1, developed once, dichloromethane:ethanol=10:1, developed once; 0.25 mm1 plate, dichloromethane:ethyl acetate=3:1, developed once, dichloromethane:ethyl acetate=1:1, developed once; and then 0.25 mm*1 plate, hexane:ethyl acetate:ethanol=10:5:1, developed twice) to give the titled compound (2.9 mg, 45%) as a colorless oil. [0686] IR(neat): 3384, 2968, 2928, 2848, 1728, 1448, 1368, 1240, 1160, 1056 cm-1. 1H NMR delta: 0.82 (s, 3H), 1.41 (d, J=7.0 Hz, 3H), 1.44 (s, 9H), 1.84 (t, J=7.3 Hz, 2H), 2.32 (t, J=7.3 Hz, 2H), 2.45 (dt, J=3.3, 7.3 Hz, 2H), 2.55-2.65 (m, 1H), 2.75-2.86 (m, 1H), 3.44 (q, J=7.0 Hz, 1H), 4.19-4.30 (m, 1H), 4.40-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.10 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 470 (M+-H2O), 57 (100%). UV lambdamaxnm: 263.

Reference： [1]Patent: US2004/19023,2004,A1 .Location in patent: Page/Page column 60

15
2-hydroxy-6-[(5-hydroxypentyl)oxy]benzenepropanoic acid methyl ester [ No CAS ]
[ 110661-91-1 ]
6-[(5-hydroxypentyl)oxy]-2-(4-t-butoxy-4-oxobutyloxy)benzenepropanoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.3%	With potassium carbonate; In dimethyl sulfoxide;	Part A Preparation of 6-[(5-Hydroxypentyl)oxy]-2-(4-t-butoxy-4-oxobutyloxy)benzenepropanoic Acid Methyl Ester A mixture of 2-hydroxy-6-[(5-hydroxypentyl)oxy]-benzenepropanoic acid methyl ester (2.04 g, 7.23 mmol) (as described by Cohen, N. EP Appl. 531,823), t-butyl 4-bromobutyrate (1.93 g, 8.67 mmol), and K2CO3 (2.29 g, 16.6 mmol) in DMSO (60 mL) was stirred at ambient temperatures under nitrogen for 21 h. The solids were removed by filtration and the filtrate was diluted with water (100 mL), and extracted with EtOAc (3*100 mL). The combined organic extracts were washed with water and sat. NaCl, dried (MgSO4), and concentrated to give product as a yellow oil (2.98 g). A portion (487 mg) was purified by silica gel flash chromatography (40:60 EtOAc/hexanes) to give the title compound as a colorless oil (367 mg, 73.3%). 1H NMR (CDCl3): 7.08 (t, J=8.2 Hz, 1H), 6.48 (d, J=8.2 Hz, 2H), 4.00-3.89 (m, 4H), 3.70-3.62 (m, 5H), 3.04-2.93 (m, 2H), 2.50-2.39 (m, 4H), 2.11-1.99 (m, 2H), 1.88-1.75 (m, 2H), 1.72-1.52 (m, 5H), 1.43 (s, 9H); MS: m/e 447.3 [M+Na].
73.3%	With potassium carbonate; In dimethyl sulfoxide;	Part A Preparation of 6-[(5-Hydroxypentyl)oxy]-2-(4-t-butoxy-4-oxobutyloxy)benzenepropanoic Acid Methyl Ester A mixture of 2-hydroxy-6-[(5-hydroxypentyl)oxy]-benzenepropanoic acid methyl ester (2.04 g, 7.23 mmol) (as described by Cohen, N. EP Appl. 531,823), t-butyl 4-bromobutyrate (1.93 g, 8.67 mmol), and K2CO3(2.29 g, 16.6mmol) in DMSO (60 mL) was stirred at ambient temperatures under nitrogen for 21 h. The solids were removed by filtration and the filtrate was diluted with water (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with water and sat. NaCl, dried (MgSO4), and concentrated to give product as a yellow oil (2.98 g). A portion (487 mg) was purified by silica gel flash chromatography (40:60 EtOAc/hexanes) to give the title compound as a colorless oil (367 mg, 73.3%). 1H NMR (CDCl3): 7.08 (t, J = 8.2 Hz, 1H), 6.48 (d, J = 8.2 Hz, 2H), 4.00-3.89 (m, 4H), 3.70-3.62 (m, 5H), 3.04-2.93 (m, 2H), 2.50-2.39 (m, 4H), 2.11-1.99 (m, 2H), 1.88-1.75 (m, 2H), 1.72-1.52 (m, 5H), 1.43 (s, 9H); MS: m/e 447.3 [M+Na].

Reference： [1]Patent: US6416733,2002,B1
[2]Patent: EP1293214,2003,A2

16
[ 2623-87-2 ]
[ 115-11-7 ]
[ 65868-63-5 ]
[ 110661-91-1 ]

Yield	Reaction Conditions	Operation in experiment
54%		t-Butyl 4-bromobutanoate 4-Bromobutanoic acid (8 g, 47.9 mmol) and iso-butene (60 ml) were reacted by the same procedure as described in Example 1 for the preparation of tert-butyl 6-bromohexanoate to give the title material (5.7 g, 54%) as a colorless liquid (b.p. 62-64 C./10 mmHg).

Reference： [1]Patent: US2002/68722,2002,A1

17
[ 1149-26-4 ]
[ 110661-91-1 ]
[ 238400-11-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 8h;	8.1 Step 1 : Preparation of 4 - ( ten- b u to x y ) -4- o x o b u ty I ((benzyloxy)carbonyl)-L-valinate. r - Butyl 4-bromobutyrate (0.4 g, 1.8 mmol, 0.9 equiv) and DIPEA (0.4 g, 3.0 mmol, 1.5 equiv) were added to a solution of Cbz-Val-OH 5 (0.5 g, 2.0 mmol) in CH3CN (5 mL). The reaction mixture was stirred at 80°C for 8 hours, concentrated, and redissolved in EtOAc. The resulting solution was washed with water, a saturated NaHCCE solution, and brine. The organic layer was dried over MgSCb, filtered, and concentrated to afford 4-(ferf-butoxy)-4-oxobutyl ((benzyloxy)carbonyl)-L-valinate 17 in quantitative yield, which was carried forward to the next step without further purification. NMR (500 MHz, CDCE) d 7.37 - 7.26 (m, 5H), 6.01 (d, / = 9.1 Hz, 1H), 5.13 - 5.02 (m, 2H), 4.45 (dd, /= 9.2, 6.6 Hz, 1H), 4.22 (dt, / = 11.5, 6.0 Hz, 1H), 4.11 (dt, / = 11.5, 6.0 Hz, 1H), 2.45 (qt, /= 15.2, 7.1 Hz, 2H), 2.12 (dq, /= 13.4, 6.7 Hz, 1H), 2.07 - 1.88 (m, 2H), 1.42 (s, 7H), 0.99 (dd, J = 25.0, 6.7 Hz, 6H). LCMS (ESI): m/z calculated for [C21H31NO6 + H]+ 394.22, found 394.38 [M + H]+.
	In N,N-dimethyl-formamide	A.I.11.a a) a) 4-(N-CBz-L-valyloxy) butyric acid t-butyl ester N-CBz-L-valine (16.25 g, 65 mmole) was dissolved in DMF (40 ml). To the solution was added potassium t-butoxide (7.24 g, 65 mmole). After 10 min, 4-bromobutyric acid t-butyl ester (12 g, 53 mmole) was added. The reaction mixture was kept at 65° C. for 2.5 hr and then poured into sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic phase was dried and the product was isolated with silica gel column chromatography. 20.1 g.

Reference： [1]Current Patent Assignee: XWPHARMA - WO2021/127461, 2021, A1 Location in patent: Paragraph 285-286
[2]Current Patent Assignee: MEDIVIR AB - US2002/128301, 2002, A1

18
[ 851728-86-4 ]
[ 110661-91-1 ]
[ 913368-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃;	To a solution of ethyl 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylate (20 g, 53 mmol) in DMF (100 mL) at 0 C. was added KOtBu (7.73 g, 69 mmol). The mixture was stirred at 0 C. for 45 minutes, then tert.-butyl 4-bromobutanoate (15.4 g, 69 mmol) was added at 0 C. The reaction mixture was allowed to warm to room temperature and stir overnight. The mixture was portioned between ether and saturated aqueous NH4Cl. The organic solution was washed with water and saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The residue was taken into hot cyclohexane. The mixture was allowed to stand for 72 hours. The solvent was decanted and the residue was washed with cold cyclohexane. The solid was then dried under high vacuum to yield 4-(3-tert.-butoxycarbonyl-propoxy)-1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (I-1a: 20.8 g). 1H NMR (400 MHz, CHLOROFORM-D) ppm 1.4 (s, 9H), 1.4 (t, J=7.1 Hz, 3H), 1.9 (m, 2H), 2.3 (t, J=7.5 Hz, 2H), 4.0 (t, J=5.9 Hz, 2H), 4.4 (q, J=7.1 Hz, 2H), 7.2 (m, 2H), 7.2 (m, 2H), 7.4 (m, 3H), 7.5 (m, 1H); m/z=519.0 (M+1).

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 397 - 401
[2]Patent: US2006/241100,2006,A1 .Location in patent: Page/Page column 16-17

19
1-cyclohexyl-3-(2,4-dichloro-4'-hydroxy-biphenyl-3-ylmethyl)-pyrrolidin-2-one [ No CAS ]
[ 110661-91-1 ]
4-[2',4'-dichloro-3'-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-yloxy]-butyric acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%		Example 179; 4- [2',4'-Dichloro-3 '-( 1 -cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-yloxy] - butyric acid; Place l-cyclohexyl-3-(2,4-dichloro-4'-hydroxy-biphenyl-3-ylmethyl)-pyrrolidin-2- one (Example 113) (200 mg, 0.5 mmol), sodium iodide (72 mg, 0.5 mmol), and cesium carbonate (1.25 g, 3.8 mmol) in THF (10 mL). Add tert-butyl 4-bromobutanoate (213 mg, 1.0 mmol) and stir at room temperature for 3 hours. Add dichloromethane and wash with water. Dry over sodium sulfate, filter, and concentrate. Dissolve residue in dichloromethane (5 mL) and TFA (5 mL) and stir for 30 minutes. Remove solvent and dissolve product in IM NaOH. The deprotonated carboxylic acid does not go into the aqueous layer. Bring the pH ~2 with 6M HCl and extract with dichloromethane. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (dichloromethane-5% methanol in dichloromethane) affords 158 mg (66%) the title compound as a brown solid:

Reference： [1]Patent: WO2006/49952,2006,A1 .Location in patent: Page/Page column 143-144

20
[ 326858-86-0 ]
[ 110661-91-1 ]
3,3-ethylenedioxy-17β-methoxymethoxy-7α-{4-(3-t-butoxycarboxypropoxy)phenyl}-5α-androstane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium chloride; potassium carbonate; In N,N-dimethyl acetamide; water;	(Step 6) Synthesis of 3,3-ethylenedioxy-17beta-methoxymethoxy-7alpha-{4-(3-t-butoxycarboxypropoxy)phenyl}-5alpha-androstane To an N,N-dimethylacetamide solution (0.5 ml) of 3,3-ethylenedioxy-17beta-methoxymethoxy-7alpha-(4-hydroxyphenyl)-5alpha-androstane (22.0 mg), t-butyl 4-bromobutyrate (31.3 mg), potassium carbonate (64.5 mg) and 18-crown-6 (123 mg) were added. After one hour, water was added to the reaction mixture and extraction with ethyl acetate was conducted. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate; after filtering, the solvent was distilled off at reduced pressure. Purification by silica gel column chromatography (developing solvents: ethyl acetate/n-hexane = 1/8) gave the end compound in 27.8 mg (yield, 99%). 1H-NMR(270MHz, CDCl3)delta: 0.78(3H, s), 0.90(3H, s), 1.04-2.12(22H, m), 1.46(9H, s), 2.43(2H, t, J=7.3Hz), 2.82-2.92(1H, m), 3.30(3H, s), 3.38(1H, t, J=8.4Hz), 3.80-3.94(4H, m), 3.97(2H, t, J=6.1Hz), 4.56(2H, s), 6.78(2H, d, J=8.6Hz), 7.26(2H, d, J=8.6Hz). Rf value (on silica gel plate, developing solvents: ethyl acetate/n-hexane = 1/4): 0.40

Reference： [1]Patent: EP1219631,2002,A1

21
(R)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-piperidine [ No CAS ]
[ 110661-91-1 ]
4-{(R)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-piperidin-1-yl}-butyric acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With sodium carbonate; In acetonitrile; at 50℃; for 42h;	Step 2; 4-{(R)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-piperidin-1-yl}-butyric acid tert-butyl ester; To a mixture of the product (0.300 g, 0.944 mmol) in step 1, <strong>[110661-91-1]tert-butyl 4-bromobutyrate</strong> (0.275 g, 1.23 mmol), and sodium carbonate (0.201 g, 1.90 mmol) in acetonitrile (3.8 mL) under an atmosphere of nitrogen was heated at 50 C. for around 18 h. To the reaction mixture was add more <strong>[110661-91-1]tert-butyl 4-bromobutyrate</strong> (0.150 g, 0.622 mmol), and sodium carbonate (0.201 g, 1.90 mmol), and was heat another 24 h at 50 C. The mixture was diluted with H2O (60 mL) and extracted with EtOAc (3×20 mL). The organic layer was washed with H2O (2×20 mL) and brine (20 mL), and then dried over Na2SO4. The filtrate was concentrated in vacuo to give a clear yellow oil. The oil was purified by flash chromatography to give the tert-butyl ester as a clear tan oil (0.180 g, 41%): 1H NMR (CDCl3): delta 7.25 (m, 2H), 6.91 (m, 6H), 4.02(m,1H), 3.94(m, 1H), 2.91(dt,1H, J=11.6 Hz, J=4.0 Hz), 2.73(m, 2H), 2.54(m, 1H), 2.33(m, 1H), 2.21(dt, 2H, J1=7.6 Hz, J2=2.8 Hz), 1.78(m, 4H), 1.60(m, 3H), 1.42(s, 9H), 1.35(m,1H).

Reference： [1]Patent: US2007/66820,2007,A1 .Location in patent: Page/Page column 53

22
[ 942054-63-9 ]
[ 110661-91-1 ]
[ 942054-64-0 ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium carbonate; In N,N-dimethyl-formamide; acetone; for 18h;Heating / reflux; Under argon atmosphere;	To 35 mg (0.074 mmol) of acetamido dihydromorphine butyric acid derivative (7) was added 3 mL of dichloromethane and 1 mL of trifluoroacetic acid. The reaction mixture was allowed to stir at room temperature for 30 minutes and concentrated. To the residue 10 mL of dichloromethane was added and concentrated. The residue was purified by preparative RP-HPLC using using a gradient run with acetonitrile-water containing 0.1% trifluoroacetic acid. Fractions containing the desired product were combined and concentrated followed by lyophilization to give 19mg (0.045 mmol, 63%) of desired product 8 as white powder. HR-ES (+): Calculated for C23H30N2O5; M+H 415.2228; observed 415.2227.

Reference： [1]Patent: EP1810973,2007,A1 .Location in patent: Page/Page column 9-10

23
[ 1035214-86-8 ]
[ 110661-91-1 ]
[ 1035216-96-6 ]

Yield	Reaction Conditions	Operation in experiment
93%		Exemplification of General Procedure J:; Preparation of tert-butyl 4-(4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5-yl)- lH-indol-l-yl)butanoate; <n="59"/>To a solution of 3-(3-chloro-4-isopropoxyphenyl)-5-(lH-indol-4-yl)-l,2,4-oxadiazole (0.100 g, 0.283 mmol) in DMF (0.999 ml) was added NaH (0.012 g, 0.311 mmol). After about 15 min tert-butyl 4-bromobutanoate (0.095 g, 0.424 mmol) was added and the reaction mixture was heated to about 500C. After about 24h the reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide tert-butyl 4-(4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5- yl)-lH-indol-l-yl)butanoate (0.135 g, 93%) as a colorless oil that solidified on standing. LCMS (Table 1, Method c) Rt = 3.50 min, m/z 496 (M+H)+.
93%		Exemplification of General Procedure J:; Preparation of teri-butyl 4-(4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5-yl)-l/7- indol-l-yl)butanoate; To a solution of 3-(3-chloro-4-isopropoxyphenyl)-5-(lH-indol-4-yl)-l,2,4-oxadiazole (0.100 g, 0.283 mmol) in DMF (0.999 mL) was added NaH (0.012 g, 0.311 mmol). After about 15 min tert- butyl 4-bromobutanoate (0.095 g, 0.424 mmol) was added and the reaction mixture was heated to about 50 C. After about 24 h the reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide tert-butyl 4-(4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5-yl)-lH-indol-l- yljbutanoate (0.135 g, 93%) as a colorless oil that solidified on standing. LC/MS (Table 1, Method c) Rt = 3.50 min, m/z 496 (M+H)+.

Reference： [1]Patent: WO2008/76356,2008,A1 .Location in patent: Page/Page column 57-58
[2]Patent: WO2011/71570,2011,A1 .Location in patent: Page/Page column 70

24
[ 110661-91-1 ]
[ 452-06-2 ]
[ 1043904-91-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3556 - 3561

25
[ 956486-49-0 ]
[ 110661-91-1 ]
[ 1150267-69-8 ]

Yield	Reaction Conditions	Operation in experiment
72%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 336h;	Intermediate 6 (10.47 g, 11.73 mmol) was dissolved in acetonitrile (500 ml) and tert-butyl bromoacetate (10.0 g, 44.84 mmol) and DIPEA (9.08 mg, 70.38 mmol) were added. The reaction mixture was stirred at RT for 14 days and then filtered. Evaporation of the solvent gave crude product which was purified using a Combiflash companion (120 g cartridge) eluting with 0-10% MeOH in DCM. The solid product was triturated with Et2O to give a white solid. Yield: 8.79 g (72%) LC-MS (Method 2): Rt = 2.93 min, m/z = 1036 [M+H]+
51%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 168h;Molecular sieves 4A;	Intermediate 30To a solution of Intermediate 20 (0.22 g, 0.246 mmol) in acetonitrile (10 ml) were added DIPEA (640 mul, 3.69 mmol) and 4-bromobutyric acid tert-butyl ester (550 mg, 2.0 mmol). The reaction was stirred at RT for 7 days in the presence of molecular sieves (4 A). The reaction mixture was diluted by adding acetonitrile (20 ml) and filtered to remove insoluble material. The volatiles were evaporated in vacuo and the residue was poured into water (100 ml) and extracted with <n="26"/>EtOAc (2 x 25 ml). The combined organic extracts was dried (Na2SO4) and the solvent was evaporated to obtain the crude product. The crude mixture was separated using a CombiFlash companion eluting with 0-15% MeOH in DCM.The desired product was obtained as a glassy liquid.Yield: 130 mg (51%)LC-MS (Method 2): Rt = 2.92 min, m/z = 1036 [M+H]+

Reference： [1]Patent: WO2009/60206,2009,A1 .Location in patent: Page/Page column 50-51
[2]Patent: WO2009/60158,2009,A1 .Location in patent: Page/Page column 24-25

26
[ 55-22-1 ]
[ 110661-91-1 ]
[ 1151655-32-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	In N,N-dimethyl-formamide; at 80℃; for 18h;	tert-Butyl-4-bromobutyrate (1.0 g, 4.5 mmol) was added to a stirred suspension of isonicotinic acid (0.25 g, 2.0 mmol) in DMF (2 ml) under argon and heated at 800C for 18 h. The cooled mixture was diluted with Et2O and the supernatant liquid decanted away from the resultant gummy solid. This was triturated using Et2O then dissolved in acetonitrile/water and freeze dried to give an off-white solid.Yield: 0.6 g (86%)LC-MS (Method 5): Rt = 0.44, m/z = 210 [M+H-'Buf

Reference： [1]Patent: WO2009/60206,2009,A1 .Location in patent: Page/Page column 41

27
[ 2799-17-9 ]
[ 110661-91-1 ]
[ 1073630-72-4 ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium carbonate;tetra-(n-butyl)ammonium iodide; In tetrahydrofuran; at 20℃; for 48h;	Add 2583 mg (18.69 mmol) potassium carbonate, 2780 mg (12.46 mmol) 4-bromobutyric acid tert.-butyl ester and 184 mg (0.50 mmol) tetra-n-butylammonium iodide to a solution of 936 mg (12.46 mmol) (2S)-1-aminopropan-2-ol in 10 ml THF. Stir the reaction mixture for 48 h at room temperature. After filtering-off the inorganic salts, concentrate the filtrate by vacuum evaporation. Take up the residue in dichloromethane and chromatograph on silica gel (solvent: dichloromethane/methanol/35% aqueous ammonia solution 9:1:0.1). 810 mg (30% of theor.) of the desired product is obtained. GC-MS (Method 12): Rt=4.73 min; m/z=172 (M-CH3CHOH)+ 1H-NMR (400 MHz, DMSO-d6): delta=4.39 (br. s, OH), 3.67-3.59 (m, 1H), 3.38-3.20 (br. s, NH), 2.51-2.47 (m, 2H), 2.39-2.37 (m, 2H), 2.21 (t, 2H), 1.60 (quin, 2H), 1.39 (s, 9H), 1.02 (d, 3H).

Reference： [1]Patent: US2009/318475,2009,A1 .Location in patent: Page/Page column 42

28
[ 1021853-33-7 ]
[ 110661-91-1 ]
[ 1197363-69-1 ]

Yield	Reaction Conditions	Operation in experiment
41%	With sodium iodide;caesium carbonate; In N,N-dimethyl-formamide; at 70℃;	Stage 1- tert-butyl 4-{4-[(4-[(7ft)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl]amino}-3-methoxybenzoyl)amino]piperidin-1-yl}butanoate To a solution of Intermediate C (500mg, 0.98mmol) and fe/f-butyl 4-bromobutyrate (439mg, 1.97mmol) in DMF (8mL) was added sodium iodide (295mg, 1.97mmol) and caesium carbonate (802mg, 2.46mmol). The reaction mixture was stirred at 700C overnight. Once cooled to room temperature, the reaction mixture was diluted with ethyl acetate (25mL). Water (25mL) was added and the product extracted into the organic layer. The aqueous layer was re-extracted with ethyl acetate (3 x 1OmL) and the combined organic portions were washed with water (3 x 2OmL). The crude product was concentrated onto silica. Purification on a 4g silica column using a CombiFlash Companion (Teledyne lsco Inc) (product eluted in 25% MeOH/DCM) gave the title compound as a yellow oil. (265mg, 41 %). ESMS m/z 650 [M+H]+. 1H NMR (300 MHz, <n="24"/>CDCI3) delta: 8.48 (1 H, d, J=8.5 Hz), 7.96 (1 H, s), 7.65-7.50 (2H, m), 6.65 (1 H, br. s.), 4.45 (1 H, t, J=7.4 Hz), 4.16 (1H, dd, J=7.2, 3.0 Hz), 4.05 (1H, dd, J=7.1 , 5.7 Hz), 3.91 (3H, s), 3.85-3.57 (2H1 m), 3.27 (3H, s), 3.12-3.07 (4H, m), 2.60-2.46 (2H, m), 2.42-1.82 (12H1 m), 1.72-1.57 (4H, m), 1.39 (9H1 s), 0.82 (3H, t, J=7.4 Hz).

Reference： [1]Patent: WO2009/141575,2009,A1 .Location in patent: Page/Page column 22-23

29
[ 1073630-54-2 ]
[ 110661-91-1 ]
[ 1325728-38-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide;tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water; at 0 - 20℃;Reflux;	Put 110 mg (0.29 mmol) (+)-1-[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}-propan-2-ol with 327 mg (1.47 mmol) 4-bromobutyric acid tert.-butyl ester and 20 mg (0.059 mmol) tetra-n-butylammonium hydrogensulphate in 2 ml dichloromethane and cool to 0 C. Then add 500 mul 50% sodium hydroxide solution and stir for two days at RT. Once again, add the same amounts of 4-bromobutyric acid tert.-butyl ester, tetra-n-butylammonium hydrogensulphate and 50% sodium hydroxide solution and stir for a further 24 h at RT. Then heat under reflux for 24 h. Leave to cool, and dilute with dichloromethane and water. Acidify with 10% citric acid solution and separate the phases. Re-extract the aqueous phase once with dichloromethane. Combine the organic phases, wash once with satd. sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Purify the residue by preparative HPLC. Dissolve the product thus obtained (30 mg) in 1 ml dichloromethane. Add 250 mul trifluoroacetic acid and stir overnight at RT. Then concentrate by evaporation and purify the residue chromatographically on a silica-gel thick-layer plate (solvent: dichloromethane/methanol 95:5). Extract the product zone with dichloromethane/methanol 9:1. 25 mg (21.2% of theor.) of the target compound is obtained.LC-MS (Method 7): Rt=3.64 min; m/z=462 (M+H)+ 1H-NMR (400 MHz, CDCl3): delta=8.39 (s, 1H), 7.51 (m, 2H), 7.41 (d, 2H), 7.26 (m, 3H), 7.06 (d, 2H), 5.12 (t, 1H), 3.89 (s, 3H), 3.77-3.70 (m, 1H), 3.55-3.47 (m, 1H), 3.42-3.38 (m, 1H), 3.28-3.20 (m, 2H), 2.31 (t, 2H), 1.76-1.67 (m, 2H), 1.09 (d, 3H).[alpha]D20=-20.0, c=0.077, acetonitrile.

Reference： [1]Patent: US2009/318475,2009,A1 .Location in patent: Page/Page column 68-69

30
[ 1192731-79-5 ]
[ 110661-91-1 ]
[ 1192732-11-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	N-[cis-3-[(4-chlorophenyl)sulfonyl]-3-(2,5-diflupsilonorophenyl)cyclobutyl]-l .1,1- trifluoromethanesulfonaniide (190 mg, 0.388 mmol) was added to DMF (1.1 mL) and treated with potassium carbonate (59 mg, 0.427 mmol), tert -butyl 4-bromobutanoate (95 mg, 0.427 mmol). The mixture was heated to 80 C and stirred for 16 hours. The reaction was cooled to ambient temperature, diluted with ethyl acetate, and washed with 1/2 saturated brine solution twice. The organic layer was dried over anhydrous magnesium sulfate, filtered then concentrated in vacuo. The residue was purified by MPLC ( 0-30 % EtOAc:Hept) to give the title compound. MS: cal'd 654 (M Na+), exp 654 (M Na+)
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	Intermediate P Tert-Butyl 4-[3-((4-cblorophenyl)suIfonyl]-3-(2,5 dii1uorophenyl)cycIobutyl][(trifIuororaethyl) suIfonyI]aniiDo}butanoateN-[cis-3-[(4-chlorophenyl)supsilonlfonyl]-3-(2,5-difluorophenyl)cyclobutyl]-l ,1,1- triflupsilonoromethanesupsilonlfonamide (190 mg, 0.388 mmol) was added to DMF (1.1 mL) and treated <n="28"/>with potassium carbonate (59 mg, 0.427 mmol), tert -butyl 4-bromobutanoate (95 mg, 0.427 mmol). The mixture was heated to 80 C and stirred for 16 hours. The reaction was cooled to ambient temperature, diluted with ethyl acetate, and washed with 1/2 saturated brine solution twice. The organic layer was dried over anhydrous magnesium sulfate, filtered then concentrated in vacuo. The residue was purified by MPLC ( 0-30 % EtOAc:Hept) to give the title compound. MS: cal'd 654 (M Na+), exp 654 (M Na+)

Reference： [1]Patent: WO2010/68564,2010,A1 .Location in patent: Page/Page column 23
[2]Patent: WO2009/131906,2009,A1 .Location in patent: Page/Page column 25-26

31
[ 1080027-75-3 ]
[ 110661-91-1 ]
[ 1080027-76-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	In tetrahydrofuran; at 50℃; for 36h;	Compound 2 (2.0 g, 6.9 mmol) was dissolved in 50 mL of dry THF. To the solution 4-bromobutanoic acid ten-butyl ester (3.1 g, 13.8 mmol) was added and the reaction mixture was stirred at 50 C. for 36 h. The product was filtered, washed with excess dry THF, and dried under vacuum to yield M2 as a colorless powder. Yield=65%. 1H NMR (300 MHz, CD3OD) delta: =0.88 (q, J=6.7 Hz, 6H), 1.48 (s, 9H), 2.04 (m, 2), 2.29 (m, 1H), 2.43 (t, J=6.6 Hz, 2H), 2.9 (m, 2H), 3.19 (m, 6H), 3.45 (m, 4H), 3.72 (m, 2H), 3.91 (t, J=7.2 Hz, 2H), 4.67 (d, J=9.2 Hz, 1H), 6.48 (m, 2H). 13C NMR (75 MHz, CD3OD) delta: 19.8, 24.3, 25.2, 29.2, 30.1, 32.8, 33.7, 46.4, 52.8, 61.5, 65.3, 83.0, 121.9, 139.1, 139.8, 147.1, 173.8 (ester, -CO), 179.7 (imide, -CO). HR-MS (FAB): calculated 431.59, found 431.29.

Reference： [1]Patent: US2010/317870,2010,A1 .Location in patent: Page/Page column 40-41; 42

32
[ 1258010-49-9 ]
[ 110661-91-1 ]
[ 1258010-66-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; toluene; acetonitrile; at 70℃; for 41h;	Example 134: 4-(4-(5-(1 -cvclohexyl-5-(methoxymethyl)-1 H-pyrazol-4-yl)-1 ,2,4-oxadiazol- 3-yl)phenoxy)butanoic acid Step 1 : tert-butyl 4-(4-(5-(1 -cyclohexyl-5-(methoxymethyl)- 1 H-pyrazol-4-yl)-1 , 2, 4-oxadiazol-3- yl)phenoxy)butanoate; To a solution of Example 123 (124 mg; 0.35 mmol) and tetrabutylammonium hydrogen sulfate (12 mg; 0.035 mmol) in toluene (0.9 ml.) was added a solution of sodium hydroxide (560 mg; 14.0 mmol) in water (0.9 ml.) followed by te/f-butyl 4-bromobutanoate (89 mg; 0.40 mmol). The mixture was heated to 70 0C for 18 hours. MeCN (1 ml.) and an additional portion of te/f-butyl 4-bromobutanoate (178 mg; 0.80 mmol) was added and the mixture was heated to 70 0C for 5 hours. A third portion of te/f-butyl 4-bromobutanoate (178 mg; 0.80 mmol) was added and the mixture was heated to 70 0C for 18 hours. DCM (10 ml.) was added and the mixture passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified on a Biotage 12+M column, eluting with petrol containing increasing amounts of EtOAc to give te/f-butyl 4-(4-(5-(1-cyclohexyl-5-(methoxymethyl)-1 H-pyrazol-4- yl)-1 ,2,4-oxadiazol-3-yl)phenoxy)butanoate as a white solid (139 mg, 80 %).1H NMR (CDCI3, 400MHz) delta 8.12 (1 H, s), 8.06 (2 H, d, J = 8.7 Hz), 6.99 (2 H, d, J = 8.7 Hz), 5.03 (2 H, s),4.36-4.23 (1 H, m), 4.07 (2 H, t, J = 6.2 Hz), 3.42 (3 H, s), 2.45 (2 H, t, J = 7.3 Hz), 2.15-2.04 (2 H, m), 2.11-1.90 (6 H, m), 1.81-1.68 (1 H, m), 1.46 (9 H, s), 1.47-1.26 (3 H, m). LC/MS: 497 (M+H)+. HPLC (Method J) Rt = 25.85 min (Purity: 97.6 %).

Reference： [1]Patent: WO2010/142628,2010,A1 .Location in patent: Page/Page column 173

33
[ 59854-12-5 ]
[ 110661-91-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2019,vol. 17,p. 3861 - 3867
[2]Journal of the American Chemical Society,2011,vol. 133,p. 958 - 963

34
[ 773021-89-9 ]
[ 110661-91-1 ]
[ 1354910-09-0 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; potassium iodide; In acetonitrile; for 16h;Reflux;	4-[2-(4-Bromo-phenyl)-6,7-dihydro-4H-furo[3,2-c]pyridine-5-yl]-butyric acid t-butyl ester (7d). Compound 6 (Rb=H, 4.55g, 16.3mmol) was suspended in acetonitril (55ml). To this suspension were added potassium carbonate (4.52g, 32.7 mmol), t-butyl 4-bromobutanoate (4.38g, 19.6mmol, 1.2eq) and potassium iodide (3.2g, 19.6mmol, 1.2eq). The mixture was heated to reflux for 16hrs after which time TLC analysis (diethyl ether/petroleum ether, 1/1, v/v, Rf 0.1) revealed complete reaction. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed with 5% NaHCOe (2x60ml). The organic layer was dried on Na2SC>4, concentrated in vacuo and the residue was purified by silica gel column chromatography (diethyl ether/petroleum ether, 1/1, v/v) to yield 7d (Rb=H, 4.94g, 71%) as a yellow solid. LC-MS (Method A): Rt 1.37, [M+H] 420.

Reference： [1]Patent: WO2012/4373,2012,A1 .Location in patent: Page/Page column 42

35
[ 885272-77-5 ]
[ 110661-91-1 ]
[ 1354910-14-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	4-[2-(4-Bromo-phenyl)-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl]-butyric acid t-butyl ester (21d, Rb=H). Compound 20 (Rb=H, 2.5g, 7.92mmol) was suspended in DMF (40ml). To this suspension was added potassium carbonate (3.8g, 27.7mmol, 3.5eq) and t-butyl 4-bromobutanoate (5.3g, 23.7mmol, 3eq). The mixture was heated at 80C for 16hrs after which time TLC analysis revealed complete reaction. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: diethyl ether/petroleum ether, 1/1, v/v to 100% diethyl ether) to yield 21d (Rb=H, 3.15g, 94%) as a white solid.

Reference： [1]Patent: WO2012/4373,2012,A1 .Location in patent: Page/Page column 46

36
[ 1355087-94-3 ]
[ 110661-91-1 ]
[ 1355089-42-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; In acetonitrile; at 65℃;	Tert-butyl 4-{6-hydroxy-2H-spiro[l-benzofuran-3,4'-piperidine]-l'- yl}butanoate. To a suspension of 2H-spiro[l-benzofuran-3,4'-piperidin]-6-ol (2 g; 9.74 mmol) in CH3CN (50 mL) was added potassiumcarbonate (4.04 g; 29.23 mmol), followed by 4-bromo-butyric acid tert-butyl ester (2.39 g; 10.72 mmol) (prepared according to Tetrahedron, 1992, 48 (42), 9277). The resulting mixture was heated at 65C overnight.After cooling to RT, the reaction mixture was partitioned between 5% aqueous NaHC03 solution and EtOAc. The layers were separated and the organic layer was dried (Na2S04), filtered, and concentrated. The residue was purified by column chromatography (S1O2, Et20) to afford the product (2.95 g, 75%).NMR (400 MHz, CDCM) delta ppm 6.93 (d, J =8.0 Hz, 1H), 6.33 (dd, J =8.0, 2.1 Hz, 1H), 6.30 (d, J =2.1 Hz, 1H), 5.80 (bs, 1H), 4.35 (s, 2H), 2.89 - 2.94 (m, 2H), 2.35 - 2.41 (m, 2H), 2.26 (t, J =7.4 Hz, 2H), 1.89 - 2.07 (m, 4H), 1.77 - 1.86 (m, 2H), 1.67 - 1.74 (m, 2H), 1.45 (s, 9H). Rt 1.08 min (System B), [M+H] + 348.1

Reference： [1]Patent: WO2012/4378,2012,A1 .Location in patent: Page/Page column 10-104
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 459 - 465

37
[ 1355087-72-7 ]
[ 110661-91-1 ]
[ 1355087-87-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; potassium iodide; In acetonitrile; at 75℃;	Tert-butyl 4-(6-(heptyloxy)-2H-spiro[benzofuran-3,4'-piperidin]-l'- yl)butanoate. 6-(Hexyloxy)-2H-spiro[l-benzofuran-3,4'-piperidine] hydrochloride (700 mg; 2.06 mmol) was suspended in CH3CN (15 mL) and t- butyl- 4-bromobutyrate (551 mg; 2.47 mmol) was added followed by K2CO3 (684 mg; 4.12 mmol) and KI (342 mg; 2.47 mmol) and the solution was stirred at 75 C overnight. The solution was allowed to cool to RT and concentrated. The residue was taken up in EtOAc and H2O. The organic phase was dried(Na2S04), filtered and concentrated to give the product (890 mg, 97%). NMR (300 MHz, CDCI3) delta ppm 6.96 (d, J =9 Hz, 1H), 6.42 (dd, J = 9 Hz, 2 Hz, 1H), 6.37 (d, J =2 Hz, 1H), 4.36 (s, 2H), 3.9 (t, J =7.5 Hz, 2H), 2,95-2.85 (m, 2H), 2.4-2.3 (m, 2H), 2.24 (t, J = 8 Hz, 2H), 2.12-1.87 (m, 4H), 1.87-1.63 (m, 6H), 1.45 (s, 9H), 1.5-1.22 (m, 8H), 0.89 (t, J =7.5 Hz, 3H).

Reference： [1]Patent: WO2012/4378,2012,A1 .Location in patent: Page/Page column 44-45

38
[ 173900-45-3 ]
[ 110661-91-1 ]
[ 1391465-56-7 ]

Yield	Reaction Conditions	Operation in experiment
		a) A mixture of 3-chloro-4-hydroxy-5-methyl-benzonitrile (1 .15 g, 6.87 mmol) and Cs2C03 (13.43 g, 41.2 mmol) in DMF (45 ml.) is stirred at rt for 30 min before tert.-butyl 4- bromobutanoate (1 .55 g, 6.95 mmol) is added. The orange suspension is stirred at 65C for 72 h. Another portion of tert.-butyl 4-bromobutanoate (1 .55 g, 6.95 mmol) is added and stirring is continued at 65C for 24 h. The mixture is dilued with water (150 ml.) and extracted three times with DCM (3x50 ml.) and EA (3x50 ml_). The org. extracts are combined, dried over MgS04, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:EA:methanol to give tert-butyl 4-(2-chloro-4-cyano- 6-methylphenoxy)butanoate (645 mg) as a colourless oil; LC-MS: tR = 1 .01 min, [M+H]+ = no mass detectable; 1 H NMR (D6-DMSO): delta 7.94 (d, J = 1 .7 Hz, 1 H), 7.75 (d, J = 1.3 Hz, 1 H), 3.95 (t, J = 6.3 Hz, 2 H), 2.46 (t, J = 7.2 Hz, 2 H), 2.30 (s, 3 H), 1.98 (quint, J = 6.6 Hz, 2 H), 1 .41 (s, 9 H).
645 mg	With caesium sulfite; In N,N-dimethyl-formamide; at 65℃; for 96h;	a) A mixture of 3-chloro-4-hydroxy-5-methyl-benzonitrile (1.15 g, 6.87 mmol) and Cs2CO3 (13.43 g, 41.2 mmol) in DMF (45 mL) is stirred at rt for 30 min before tert.-butyl 4-bromobutanoate (1.55 g, 6.95 mmol) is added. The orange suspension is stirred at 65 C. for 72 h. Another portion of tert.-butyl 4-bromobutanoate (1.55 g, 6.95 mmol) is added and stirring is continued at 65 C. for 24 h. The mixture is dilued with water (150 mL) and extracted three times with DCM (350 mL) and EA (350 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:EA:methanol to give tert-butyl 4-(2-chloro-4-cyano-6-methylphenoxy)butanoate (645 mg) as a colourless oil; LC-MS: tR=1.01 min, [M+H]+=no mass detectable; 1H NMR (D6-DMSO): delta 7.94 (d, J=1.7 Hz, 1H), 7.75 (d, J=1.3 Hz, 1H), 3.95 (t, J=6.3 Hz, 2H), 2.46 (t, J=7.2 Hz, 2H), 2.30 (s, 3H), 1.98 (quint, J=6.6 Hz, 2H), 1.41 (s, 9H).

Reference： [1]Patent: WO2012/98505,2012,A1 .Location in patent: Page/Page column 48
[2]Patent: US2013/303514,2013,A1 .Location in patent: Paragraph 0264

39
[ 37964-17-3 ]
[ 110661-91-1 ]
[ 1400927-58-3 ]

Yield	Reaction Conditions	Operation in experiment
77%		Step No.2: Ethyl 1-(4-tert-butoxy-4-oxobutyl)-1H-pyrrole-3-carboxylate (177)A solution of ethyl 1H-pyrrole-3-carboxylate (176) (7.6 g, 55 mmol) in DMF (273 mL) was cooled in an ice bath and then treated with NaH (60% dispersion in mineral oil; 3.3 g, 82 mmol). Once gas evolution had subsided, the suspension was heated at about 50 C. for about 1 h. tert-Butyl 4-bromobutanoate (14 mL, 82 mmol) was added and stirring was continued at 50 C. for 16 h. The reaction was concentrated under reduced pressure and the residue was partitioned between EtOAc (250 mL) and water (250 mL). After separating the layers, the organic phase was washed with saturated aqueous NaCl (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (330 g) using a gradient of 0-50% EtOAc in heptane to yield ethyl 1-(4-tert-butoxy-4-oxobutyl)-1H-pyrrole-3-carboxylate (177) (11.8 g, 77%). LC/MS, method 3, Rt=2.42 min, MS m/z 282 (M+H)+. 1H NMR (400 MHz, CDCl3) delta 7.27-7.26 (m, 1H), 6.60-6.55 (m, 2H), 4.30-4.19 (m, 2H), 3.93 (t, J=6.8 Hz, 2H), 2.21-2.15 (m, 2H), 2.12-1.98 (m, 2H), 1.45 (s, 9H), 1.36-1.30 (t, J=7.1 Hz, 3H).

Reference： [1]Patent: US2012/238549,2012,A1 .Location in patent: Page/Page column 157

40
[ 19438-10-9 ]
[ 110661-91-1 ]
[ 1448189-94-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 22h;	Methyl 3-(4-(tert-butoxy)-4-oxobutoxy)beiizoate A solution of methyl 3Thydroxybenzoate (commercially available from for example Aldrich) (1 g, 6.6 mmol) and K2C03 (1.82 g, 13.2 mmol) in DMF (10 mL) was treated with tert-butyl 4-bromobutanoate (commercially available from for example Aldrich) (2.2 g, 9.9 mmol) and the mixture was stirred at 60 C for 16 hours. A further aliquot of K2C03 (1.82 g, 13.2 mmol) and tert-butyl 4-bromobutanoate (2.2 g, 9.9 mmol) were added and the mixture was heated at 60 C for further 6 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with brine (2 x 50 mL), dried (hydrophobic frit) and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution from 0% to 100% methyl tert-butyl ether in cyclohexane to afford the title compound (1.4 g, 4.8 mmol, 72 % yield). LCMS RT= 1.26 min, ES+ve m/z 312 [M+H]+.
72%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 22h;	A solution of methyl 3-hydroxybenzoate (commercially available from for example Aldrich) (1 g, 6.6 mmol) and K2CO3 (1.82 g, 13.2 mmol) in DMF (10 mL) was treated with tert-butyl 4-bromobutanoate (commercially available from for example Aldrich) (2.2 g, 9.9 mmol) and the mixture was stirred at 60 C. for 16 hours. A further aliquot of K2CO3 (1.82 g, 13.2 mmol) and tert-butyl 4-bromobutanoate (2.2 g, 9.9 mmol) were added and the mixture was heated at 60 C. for further 6 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with brine (2×50 mL), dried (hydrophobic fit) and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution from 0% to 100% methyl tert-butyl ether in cyclohexane to afford the title compound (1.4 g, 4.8 mmol, 72% yield). LCMS RT=1.26 min, ES+ve m/z 312 [M+H]+.

Reference： [1]Patent: WO2013/106646,2013,A2 .Location in patent: Page/Page column 191-192
[2]Patent: US2014/356322,2014,A1 .Location in patent: Paragraph 0433
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 5148 - 5175

41
[ 1466574-65-1 ]
[ 110661-91-1 ]
[ 1466574-62-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2.5h;	To a solution of 3-mercapto-5-trifluoromethyl-benzoic acid methyl ester (990 mg, 4.19 mmol) in acetonitrile (25 mL) were added N,N-diisopropylethylamine (1.08 g, 1.46 mL, 8.38 mmol) and tert-butyl 4-bromobutanoate (935 mg, 4.19 mmol, CAS RN 110611-91-1). The clear yellow solution was stirred at room temperature for 2.5 hours and then poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow liquid (1.27 g, 80%). MS (ESI+): m/z=379 ([M+]).
80%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2.5h;	To a solution of 3-mercapto-5-trifluoromethyl-benzoic acid methyl ester (990 mg, 4.19 mmol) in acetonitrile (25 mL) were added N,N-diisopropylethylamine (1.08 g, 1.46 mL, 8.38 mmol) and tert-butyl 4-bromobutanoate (935 mg, 4.19 mmol, CAS R 110611-91-1). The clear yellow solution was stirred at room temperature for 2.5 hours and then poured on water and ethyl acetate and the layers were separated. The aqueos layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n- heptane : ethyl acetate (100 : 0 to 70 : 30). Light yellow liquid (1.27 g, 80%). MS (ESI+): m/z = 379 ([M+]).

Reference： [1]Patent: US2013/267519,2013,A1 .Location in patent: Paragraph 0249
[2]Patent: WO2013/149977,2013,A1 .Location in patent: Page/Page column 55

42
[ 110661-91-1 ]
[ 13906-09-7 ]
[ 1507362-29-9 ]

Yield	Reaction Conditions	Operation in experiment
66.1%	With potassium carbonate; In acetone; at 60℃; for 4h;	To a mixture of 2-mercapto-4(3H)-quinazolinone (0.706 g, 3.96 mmol) and potassium carbonate (1.094 g, 7.92 mmol) in acetone was added tert- butyl 4-bromobutanoate (1.06 g, 4.75 mmol). The mixture was stirred at 60C for 4 h (LC-MS showed complete conversion to the desired product). The solid was filtered off and the solution was concentrated. The residual material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 40% EtOAc in hexane, to provide tert- butyl 4-((4-oxo-3,4-dihydroquinazolin-2-yl)thio)butanoate (0.839 g, 2.62 mmol, 66.1 % yield) as white solid. lH NMR (400 MHz, DMSO-i/6) delta ppm 12.54 (s, 1 H) 8.04 (dd, J=7.92, 1.17 Hz, 1 H) 7.77 (ddd, J=8.31, 7.04, 1.66 Hz, 1 H) 7.52 (d, J=7.82 Hz, 1 H) 7.42 (ddd, J=8.00, 7.07, 1.08 Hz, 1 H) 3.25 (t, J=7.14 Hz, 2 H) 2.37 (t, J=7.29 Hz, 2 H) 1.94 (quin, J=7.24 Hz, 2 H) 1.41 (s, 9 H). m/z (ESI) 321.2.

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 10003 - 10015
[2]Patent: WO2014/36022,2014,A1 .Location in patent: Paragraph 0187

43
ethyl 3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate [ No CAS ]
[ 110661-91-1 ]
ethyl 3-((1-(1-(4-(tert-butoxy)-4-oxobutyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With caesium carbonate; In N,N-dimethyl-d6-formamide; at 20℃; for 16h;Inert atmosphere; Cooling with ether-dry ice;	Step 1: Synthesis of ethyl 3-((1-(1-(4-(tert-butoxy)-4-oxobutyl)- 1H-pyrazol-4-yl)-6-chloro-2- cyclopropyl-7-fluoro- 1H-indol-3-yl)thio)-2-fluorobenzoate (2):1003731 To a stirred solution of indole 1 (Example 11, Step 3; 200 mg, 0.42 mmol) in DMF (5 mL) under inert atmosphere were added Cs2CO3 (206 mg, 0.63 mmol) and tert-butyl 4- bromobutanoate (141 mg, 0.63 mmol) at RT and stirred for 16 h. The mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried (Na2504), filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel chromatography; 20% EtOAc/ hexanes) to afford compound 2 (180 mg, 70%) as a pale brown oil. 1H NMR (400 MHz, CDC13): 5 7.67 (s, 1H), 7.64 (s, 1H), 7.63-7.60 (m, 1H), 7.18 (d,J= 8.4 Hz, 1H), 7.10-7.06 (m, 1H), 6.93 (t,J 8.0 Hz, 1H), 6.77 (t,J 7.6 Hz, 1H), 4.41 (q, 2H), 4.28 (t,J= 6.8 Hz, 2H), 2.28-2.19 (m, 4H), 1.74-1.66 (m, 1H), 1.46 (s, 9H),1.41 (t, J= 7.2 Hz, 3H), 1.06-1.02 (m, 2H), 0.89-0.84 (m, 2H); LC-MS (ES): m/z 618.6 (M + Hj.

Reference： [1]Patent: WO2015/77503,2015,A1 .Location in patent: Paragraph 00373

44
2-{6-amino-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-yl}-N-benzylacetamide [ No CAS ]
[ 110661-91-1 ]
tert-butyl 4-({2-[(benzylcarbamoyl)methyl]-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}amino)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With tetra-(n-butyl)ammonium iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃;	This was prepared as per 25e from 24 using t-butyl 4-bromobutanoate. Yield 21%. 1H NMR (300 MHz, CHLOROFORM-d) d7.18-7.33 (m, 3H), 7.09 (d,J= 6.78 Hz, 2H), 6.98 (br s, 1H), 6.87 (d,J= 8.29 Hz, 1H), 6.65-6.73 (m, 2H), 6.58-6.64 (m, 1H), 6.46 (dd,J= 2.17, 8.19 Hz, 1H), 6.33 (d,J= 2.07 Hz, 1H), 4.47 (dd,J= 8.01,14.98 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.54-3.69 (m, 2H), 3.32-3.47 (m, 1H), 3.14 (t,J= 6.88 Hz, 2H), 3.07-3.32 (m, 2H), 2.76-2.99(m, 4H), 2.41-2.54 (m, 1H), 2.34 (t, J= 7.16 Hz, 2H), 1.90 (quin,J= 7.02 Hz, 2H), 1.46 (s, 9H).m/z588 (M+H)

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5709 - 5724

45
tert-butyl 3-(1-((3-(2-aminoethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate [ No CAS ]
[ 110661-91-1 ]
tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3-(2-((4-(tert-butoxy)-4-oxobutyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Diethyl vinylphosphonate; In dichloromethane; at 50℃;Sealed tube;	[000730] To a solution of Example 1.2.7 (0.103 g) and tert-butyl 4-bromobutanoate (0.032 g) in dichloromethane (0.5 inL) was added N,N-diisopropylethylamine (0.034 mL) at 50 C in a sealed amber vial overnight. The reaction was concentrated, dissolved in dimethyl sulfoxide/methanol (1 : 1, 2 mL) and purified by reverse phase HPLC using a Gilson system, eluting with 5-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 944.6 (M+l).
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 50℃;Sealed tube;	To a solution of Example 1.2.7 (0.103 g) and tert-butyl 4-bromobutanoate (0.032 g) in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (0.034 mL) at 50 C in a sealed amber vial overnight. The reaction was concentrated, dissolved in dimethyl sulfoxide/methanol (1:1, 2 mL) and purified by reverse phase HPLC using a Gilson system, eluting with 5-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 944.6 (M+1).
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 50℃;Sealed tube;	To a solution of Example 1.2.7 (0.103 g) and tert-butyl 4-bromobutanoate (0.032 g) in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (0.034 mL) at 50 C. in a sealed amber vial overnight. The reaction was concentrated, dissolved in dimethyl sulfoxide/methanol (1:1, 2 mL) and purified by reverse phase HPLC using a Gilson system, eluting with 5-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 944.6 (M+1).

Reference： [1]Patent: WO2016/94509,2016,A1 .Location in patent: Paragraph 000730
[2]Patent: WO2017/214462,2017,A2 .Location in patent: Page/Page column 492
[3]Patent: US2017/355769,2017,A1 .Location in patent: Paragraph 1708

46
2-(4-(benzyloxy)-3-methylphenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine [ No CAS ]
[ 110661-91-1 ]
4-(2-(4-(benzyloxy)-3-methylphenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		Compound IXc (56 mg; 0.169 mmol; 1 eq) was dissolved in DMF (2 mL). NaH (9.76mg; 0.20 mmol; 1.2 eq; 50% in oil) was added under stirring and argon. Themixture was stirred for lh at RT. Tert-butyl 4-bromobutanoate (56.7 mg; 0.254 mmol; 1.5 eq) was added and the mixture was stirred for 20h at RT during which half of the starting materials were reacted. A further 10 mg naH (50% in oil), followed by stirring at RT for 30 mm and addition of a further 60 mg tert-butyl 4-bromobutanoate. The mixture was stirred for 5h at 50C. The DMF was evaporated and the residue was extracted with water and DCM. The organic phase was washed twice with water, dried with MgSO4 and evaporated. The residue was purified by flash chromatography (silica gel, DCM/MeOH 95:5) giving the product with a yield of 63mg (0.133 mmol; 79%).

Reference： [1]Patent: WO2017/36978,2017,A1 .Location in patent: Page/Page column 139

47
[ 60-27-5 ]
[ 110661-91-1 ]
C₁₂H₂₁N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	In N,N-dimethyl-formamide; at 90℃;	1) 12.0 g (88.4 mmol) of compound 1 and 19.7 g (88.4 mmol) of t-butyl bromobutyrate were weighed out,Were dissolved in 120 mL of dimethylformamide (DMF)The solution was then heated to 90 C,overnight.To this solution was added 350 mL of ethyl acrylate (EA)The reaction mixture was stirred for 25min at 4 .The solid precipitate in the solution is filtered out,Washed with acetone and dried in vacuo,To give 5.05 g of compound 2 as a white solid,Yield 24%.

Reference： [1]Patent: CN104557722,2017,B .Location in patent: Paragraph 0065; 0066

48
[ 3359-49-7 ]
[ 110661-91-1 ]
tert-butyl (E)-4-(3-benzylidene-2-oxoindolin-1-yl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		To triphenylphosphine (1.3 g, 5 mmol) in 10 ml of toluene was added benzyl bromide 20 (0.6 ml, 5 mmol) via syringe, the reaction was heated at 110 C for 15 h, then the mixture was cooled to room temperature and the solid formed was isolated by suction filtration, washed with diethyl ether (3 x 5 ml) and dried in vacuo to give a white solid. Under an atmosphere of argon, 10 ml of anhydrous THF was added and the solution was cooled to 0 C. A solution of butyl lithium (2.5 M in hexanes, 2 ml, 5 mmol) was added dropwise via syringe and the reaction was allowed to stir for lh in order to form 21. A solution of isatin 22 (0.75 g, 5 mmol) in dry THF (30 ml) was added dropwise via syringe over 20 min at 0 C and the resulting solution was allowed to stir at room temperature for 15 h. The reaction mixture was then poured into a saturated solution of NC1 (35 ml) at 0 C and extracted with dichloromethane (3 x 25 mL). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated in vacuo to afford a residue containing a E/Z mixture (ca. 4: 1) of product 3- benzylideneindolin-2-one 23 that was separated by flash column chromatography, eluting with 3:7 EtOAc in hexanes, to give (E)-23 (605 mg, 62%) and (Z)-23 (155 mg, 15%) as yellow solids. To a solution of 3-benzylideneindolin-2-one 23 (130 mg, 0.6 mmol) in 10 ml of DMF was added potassium carbonate (207 mg, 1.5 mmol). The reaction was stirred at room temperature for 15 minutes, tert- Butyl-4-bromobutyrate 24 (212 iL, 1.2 mmol) was then added. The reaction was stirred at room temperature overnight, concentrated in vacuo, dissolved in EtOAc and washed with 0. The layers were separated and the aqueous layer was extracted with additional EtOAc. The combined organic phase was dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with 3:7 EtOAc in petroleum ether, to give the product teri-butyl 4-(3-benzylidene-2 -oxoindolin-l -yl)butanoate 25 as an orange solid (83%, 180 mg) (Figure 15).

Reference： [1]Patent: WO2017/108741,2017,A1 .Location in patent: Page/Page column 22-23

49
[ 110661-91-1 ]
[ 162155-27-3 ]
tert-butyl 4-(3-amino-5-methoxyphenoxy)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27 g	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 65h;	To a mechanically stirred solution of terf-butyl 4-bromobutanoate [CAS 1 10661 - 91 -1] (42.3 g, 0.19 mol) in DMF (600 mL) was added in portions a solid mixture of 3-amino-5-methoxyphenol [CAS 162155-27-3] (26.4 g, 0.19 mol) and Cs2CO3 (123.6 g, 0.379 mol). The reaction was stirred at 60C for 65 h, and allowed to reach room temperature. The mixture was poured out into H2O (2.5 L). The product was extracted with Et2O (2 times). The combined organic layers were washed with brine, dried over MgSO4 and filtered off. The solvent was evaporated under reduced pressure, and then co-evaporated with toluene. The residue was purified via Normal Phase HPLC (Stationary phase: silica gel 60A 25-40 muiotatauiota (Merck), Mobile phase: gradient from 20% EtOAc, 80% heptane to 60% EtOAc, 40% heptane) yielding te/t-butyl 4-(3-amino-5-methoxyphenoxy)butanoate 1a (27 g).
27 g	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 65h;	To a mechanically stirred solution of terf-butyl 4-bromobutanoate [CAS 1 10661 -91 - 1] (42.3 g, 0.19 mol) in DMF (600 ml_) was added in portions a solid mixture of 3-amino-5-methoxyphenol [CAS 162155-27-3] (26.4 g, 0.19 mol) and Cs2CO3 (123.6 g, 0.379 mol). The reaction was stirred at 60C for 65 h, and allowed to reach room temperature. The mixture was poured out into H2O (2.5 L). The product was extracted with Et.20 (2 times). The combined organic layers were washed with brine, dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure, and co-evaporated with toluene. The residue was purified via Normal Phase HPLC (Stationary phase: silica gel 60A 25-40 muiotatauiota (Merck), mobile phase: gradient from 20% EtOAc, 80% heptane to 60% EtOAc, 40% heptane) yielding terf-butyl 4-(3-amino-5-methoxyphenoxy)butanoate 1a (27 g).

Reference： [1]Patent: WO2017/167951,2017,A1 .Location in patent: Page/Page column 14
[2]Patent: WO2018/215316,2018,A1 .Location in patent: Page/Page column 15; 16

50
8-(3-(4-(1H-pyrazol-4-yl)phenyl)-5-chloropyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one [ No CAS ]
[ 110661-91-1 ]
C₃₀H₃₆ClN₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; potassium iodide; In acetone;Reflux;	To a solution of 8-(3-(4-(lH-pyrazol-4-yl)phenyl)-5-chloropyridin-4-yl)-2,8- diazaspiro[4.5]decan-l-one (18.4 mg, 0.045 mmol) in Acetone (0.5 mL) was added ieri-butyi 4-bromobutanoate (15.1 mg, 0.068 mmol), followed by K2CG3 (12.3 mg, 0.09 mmol) and KI (11.3mg, 0.068 mmol). The mixture was then heated to reflux and kept stirring overnight. The mixture was diluted with EtOAc and H2O, extracted, and washed with brine. The organic layer was dried over anhydrous Na2S04 and concentrated. The crude was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give /-butyl ester as a gray solid (23.5 mg, 95%). I . ( VIS: m/z 550,3 j VI i \|.

Reference： [1]Patent: WO2017/185034,2017,A1 .Location in patent: Page/Page column 79; 80; 84

51
[ 36669-02-0 ]
[ 110661-91-1 ]
1,2-dimethyl 3-[4-(tert-butoxy)-4-oxobutoxy]benzene-1,2-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 18h;	Tert-butyl 4-bromobutanoate (0.81 mL, 4.57 mmol) was added to a suspension of 1 ,2- dimethyl 3-hydroxybenzene-1 ,2-dicarboxylafe (Preparation 1) (0.80 g, 3.81 mmol) and potassium carbonate (1.58 g, 11.43 mmol) in DMF (15 mL). The reaction was stirred at 50 C for 18 hours. The solvent was removed in vacuo and the crude product was dissolved in EtOAc. The organic layer was washed with brine (3x) and dried over MgS04. The solvent was removed in vacuo and the crude product was purified by column chromatography using 1 :4 EtOAc:PE to give 1 ,2-dimethyl 3-[4-(tert-butoxy)-4- oxobutoxy]benzene-1 ,2-dicarboxylate (1.29 g, 3.66 mmol, 96%) as a pale yellow solid. H NMR (400 MHz, DMSO-d6) delta ppm 7.58-7.51 (m, 2H), 7.41 (dd, J = 7.1 , 2.3 Hz, 1 H), 4.07 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.33 (t, J = 7.4 Hz, 2H), 1.92-1.83 (m, 2H), 1.40 (s, 9H). LCMS: [M+NH4]+ = 370

Reference： [1]Patent: WO2017/212329,2017,A1 .Location in patent: Page/Page column 26; 78

52
[ 76003-29-7 ]
[ 110661-91-1 ]
tert-butyl 4-(4-(tert-butoxy)-4-oxobutyl)-3-oxopiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%		Under a N2 atmosphere, NaH (219 mg, 5.99 mmol, 60% dispersion in mineral oil) was added to a stirring suspension of fert-butyl 3-oxopiperazine-l-carboxylate (1 g, 4.99 mmol) in THF (20 mL) at 0C and stirred for five minutes. Ethyl 4-bromobutanoate (1.33 g, 5.99 mmol) was added at 0C. The reaction was stirred overnight. The reaction was quenched with several drops of methanol, diluted with ethyl acetate, and washed with H20, brine, and dried over magnesium sulfate. The organic layer was concentrated in vacuo which provided the crude material as a clear oil. The crude oil was purified by flash chromatography with ethyl acetate in hexanes as the eluent to afford Intermediate 23A (364 mg, 21%) as a clear oil. LCMS (method A): m/z 343.4 (M+H)+. lH NMR (CDC13): delta 4.06 (s, 2H), 3.63 (t, 2H), 3.42 (t, 2H), 3.36 (t, 2H), 2.26 (t, 2H), 1.84 (quin, 2H), 1.46 (s, 9H), 1.44 (s, 9H).

Reference： [1]Patent: WO2018/5794,2018,A2 .Location in patent: Page/Page column 98-99

53
[ 888703-77-3 ]
[ 110661-91-1 ]
tert-butyl-4-[tert-butoxycarbonyl-[tert-butoxycarbonyl(prop-2-ynyl)amino]amino]butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of tert-butyl N-(tert-butoxycarbonylamino)-N-prop-2-ynyl-carbamate 2 (8.50 g, 31.44 mmol, 1.00eq.) in DMF (250 mL) was added Cs2CO3 (12.29 g, 37.73 mmol, 1.20 eq.) and tert-butyl 4-bromobutanoate 1(10.52 g, 47.16 mmol, 1.50 eq.). The mixture was stirred at 20 C for 16 hours. Afterwards, the reaction mixturewas diluted with H2O (1000 mL), extracted with EtOAc (4 × 300 mL), and the combined organic layers werewashed with a sat. LiCl aqueous solution (2 × 500 mL), dried over with anhydrous Na2SO4, and concentrated invacuo to give a product. The product was purified by flash silica gel chromatography (ISCO; 120 g Flash SilicaFlash Column, Eluent of 0~10% EtOAc / Petroleum ether gradient at 80 mL / min). tert-Butyl 4-[tertbutoxycarbonyl-[tert-butoxycarbonyl(prop-2-ynyl)amino]amino]butanoate 3 (12.00 g, 29.09 mmol, 92% yield) wasobtained as a light yellow oil. 1H NMR (400 MHz, CDCl3, 7.27 ppm) delta = 4.60 - 4.42 (m, 1H), 4.02 - 4.00 (m, 1H),3.53-3.39 (m, 2H), 2.31 - 2.25 (m, 3H), 1.94 - 1.92 (m, 2H), 1.48 - 1.45 (m, 27H); 13C NMR (101 MHz, CD3OD) (majorrotamer) delta = 172.77 (C), 154.61 (C), 81.17 (C), 80.09 (C), 77.83 (C), 73.35 (CH), 48.69 (CH2), 38.56 (CH2), 32.54(CH2), 27.10 (CH3), 23.11 (CH2); LCMS (ESI), calculated for C21H36N2NaO6 [M+Na]+ 435.25 observed 435.2.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1363 - 1370

54
[ 58914-34-4 ]
[ 110661-91-1 ]
tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenoxy)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;	Step 2: Preparation of tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenoxy)butanoate A flask was charged with <strong>[58914-34-4]2-hydroxy-4-(trifluoromethyl)benzaldehyde</strong> (300 mg, 1.58 mmol, 1.00 equiv), DMF (10 mL), potassium carbonate (654 mg, 4.73 mmol, 3.00 equiv), and tert-butyl 4-bromobutanoate (702 mg, 3.15 mmol, 2.00 equiv). The resulting solution was stirred overnight at 100 C. and quenched with water (30 mL). The resulting solution was extracted with DCM (250 mL) and the organic layers were combined, washed with brine (230 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/10) to provide 450 mg (86% yield) of tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenoxy)butanoate as a light yellow solid. 1H NMR (300 MHz, Chloroform-d) delta 10.5 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.29-7.33 (m, 2H), 4.22 (t, J=6.0 Hz, 2H), 2.50 (t, J=6.0 Hz, 2H), 2.18-2.25 (m, 2H), 1.49 (s, 9H).
62%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	A flask was charged with <strong>[58914-34-4]2-hydroxy-4-(trifluoromethyl)benzaldehyde</strong> (110 mg,0.580 mmol, 1.00 equiv, prepared as described in Example 7, Step 1), DMF (10 mL), tertbutyl 4-bromobutanoate (258 mg, 1.16 mmol, 2.00 equiv), and potassium carbonate (240 mg, 1.74 mmol, 3.00 equiv). The resulting solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution was extracted with EtOAc (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydroussodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/9) to provide 120 mg (62% yield) of tert-butyl 4-(2- formyl-5-(trifluoromethyl)phenoxy)butanoate as a yellow oil.

Reference： [1]Patent: US2018/134674,2018,A1 .Location in patent: Paragraph 0329; 0330
[2]Patent: WO2018/93949,2018,A1 .Location in patent: Paragraph 00293

55
C₁₆H₁₈N₂ [ No CAS ]
[ 110661-91-1 ]
[ 76-05-1 ]
C₂₀H₂₂N₂O₂*C₂HF₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%		Compound 32 was synthesized in accordance withthe following scheme. Compound 29 (31.0 mg, 0.130 mmol, 1 eq.) wasdissolved in acetonitrile (2 mE), compound 31(22.3 mg, 0.100 nmol, 0.8 eq.), N,N-diisopropylethylamine (113.3 tL,0.650 mmol, 5 eq.), and a small amount of potassium iodide were added, and the mixture was stirred for 21 hours at 60 C., and then was stirred for another 7 hours at 80 C. The mixture was returned to room temperature, and water was then added and extracted using dichloromethane, then the organic layer was washed using a saturated sodium chloride solution and dried using anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in dichioromethane (10 mE), trifluoroacetic acid (2 mE) was added, the mixture was stirred for 2 hours at room temperature, and thereafter the solvent was removed under reduced pressure. The resulting residue was dissolved in dichloromethane (5 mE) and methanol (2 mE), p-chloranil (34.1 mg, 0.139 mmol, 1.1 eq.) was added, the mixture was stirred for 30 mm. at room temperature, and the solvent was thereafier removed under reduced pressure. The resulting residue was purified by HPEC (eluent A (H20, 1% acetonitrile, 0.1% trifluoroacetic acid), eluent B (acetonitrile, 1% H20) (AB=90/10 to 0/100 40 mm)) to obtain the objective compound 29 (11.7 mg, 0.0268 mmol, 21%). 1H NMR (400 MHz, CD3OD): 1.65 (s, 6H),1.94-2.01 (m, 2H), 2.46 (t, 2H, J=7.0 Hz), 3.50 (t, 2H, J=7.2 Hz), 6.77 (dd, 1H, J=2.0, 8.7 Hz), 6.84 (d, 1H, J=8.2 Hz), 7.09 (d, 1H, J==2.0 Hz), 7.15 (br s, 1H), 7.61-7.66 (m, 2H),8.05 (s, 1H); ?3C NMR (100 MHz, CD3OD): delta 25.2, 31.7,33.6, 43.5, 114.1, 116.0, 122.2, 122.4, 141.4, 155.9, 159.6,161.2, 176.6; HRMS (ESI+): Calcd for [M]+, 323.17540, Found, 323.17538 (-0.0 mmu).

Reference： [1]Patent: US2018/52109,2018,A1 .Location in patent: Paragraph 0160; 0161; 0162; 0163

56
[ 110661-91-1 ]
[ 269409-70-3 ]
tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 12h;	Example 15 Synthetic Scheme A: Compounds 305, 298, 299, 300, 301, 302, and 303 tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanoate (1). To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (209.12 mg, 0.95 mmol) and tert-butyl 4-bromobutanoate (212 mg, 0.95 mmol) in N,N-Dimethylformamide (2 mL) was added Cs2CO3 (402.47 mg, 1.24 mmol). Reaction mixture was heated at 65 C. for 12 hours (overnight) . By TLC small amounts of starting material (Hex:AcOEt, 7:3). Crude product was purified by flash CC (SiO2-25 g, Hex:AcOEt, gradient 9:1 to 4:6) to give 198 mg (57% yield) of product as an oil: 1H NMR (500 MHz, DMSO-d6) delta 7.59 (d, J=8.2 Hz, 2H), 6.91 (d, J=7.9 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 2.35 (t, J=7.3 Hz, 2H), 1.92 (p, J=6.7 Hz, 2H), 1.39 (s, 9H), 1.27 (s, 12H). 13C NMR (101 MHz, dmso) delta 172.25, 161.56, 136.66, 114.37, 83.77, 80.12, 66.81, 31.72, 28.20, 25.12, 24.71. LC-MS (ESI); m/z [M+Na]+: Calcd. for C20H31BO5Na, 385.2162. Found 385.2194.
57%	With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 12h;	To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (209.12 mg, 0.95 mmol) and tert-butyl 4-bromobutanoate (212 mg, 0.95 mmol) in N,N-Dimethylformamide (2 mL) was added Cs2CO3 (402.47 mg, 1.24 mmol). Reaction mixture was heated at 65 oC for 12 hours (overnight) . By TLC small amounts of starting material (Hex:AcOEt, 7:3). Crude product was purified by flash CC (SiO2-25g, Hex:AcOEt, gradient 9:1 to 4:6) to give 198 mg (57% yield) of product as an oil: 1H NMR (500 MHz, DMSO-d6) d 7.59 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 7.9 Hz, 2H), 3.99 (t, J = 6.3 Hz, 2H), 2.35 (t, J = 7.3 Hz, 2H), 1.92 (p, J = 6.7 Hz, 2H), 1.39 (s, 9H), 1.27 (s, 12H).13C NMR (101 MHz, dmso) d 172.25, 161.56, 136.66, 114.37, 83.77, 80.12, 66.81, 31.72, 28.20, 25.12, 24.71. LC-MS (ESI); m/z [M+Na]+: Calcd. for C20H31BO5Na, 385.2162. Found 385.2194.

Reference： [1]Patent: US2018/179183,2018,A1 .Location in patent: Paragraph 1425
[2]Patent: WO2020/51564,2020,A1 .Location in patent: Paragraph 0697; 0698

57
[ 1829-33-0 ]
[ 110661-91-1 ]
tert-butyl 4-(3-chloro-5-formylphenoxy)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;	A 50-mL round-bottom flask was charged with <strong>[1829-33-0]3-chloro-5-hydroxybenzaldehyde</strong> (1.00 g, 6.39 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), potassium carbonate (2.65 g, 19.2 mmol, 3.00 equiv), and tert-butyl 4-bromobutanoate (2.84 g, 12.7 mmol, 2.00 equiv). The resulting solution was stirred overnight at 100 C and quenched with water (30 mL). The resulting solution was extracted with EtOAc (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with DCM/MeOH (98/2) to provide 1.10 g (5 8%) of tert-butyl 4-(3- chloro-5-formylphenoxy)butanoate as a light yellow oil.

Reference： [1]Patent: WO2018/93949,2018,A1 .Location in patent: Paragraph 00316

58
[ 1829-33-0 ]
[ 110661-91-1 ]
1,1,1,3,3,3-hexafluoropropan-2-yl 1-(3-(4-(tert-butoxy)-4-oxobutoxy)-5-chlorobenzyl)-1,8-diazaspiro[4.5]decane-8-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/93949,2018,A1

59
[ 1244781-14-3 ]
[ 110661-91-1 ]
C₂₀H₂₇F₂NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.53 g	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 2h;	10487] A solution of the Compound 1(3.67 g), the Compound 2 (3.54 g), and diisopropylethylamine (7.07 mE) in acetonitrile (15 mE) was stirred at 80 C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and then chloroform and an aqueous solution of sodium hydrogen carbonate were added thereto, and the resulting mixture was stirred, and extracted with chloroform. The resulting organic layers were dried, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography (hexane:ethyl acetate=90:1O to 65:35) to give the Compound 3 (3.53 g) as a yellow viscous material. MS (APCI): mlz 384 [M+H]
3.53 g	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 2h;	Compound 1 (3.67 g),Compound 2 (3.54 g),Diisopropylethylamine (7.07 mL)In acetonitrile (15 mL) was stirred at 80 C. for 2 hours.After concentrating the reaction mixture under reduced pressure,Chloroform and an aqueous sodium hydrogen carbonate solution were added and stirred,And extracted with chloroform.The obtained organic layer was dried and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 to 65: 35) to obtain Compound 3(3.53 g) as a yellow viscous substance.

Reference： [1]Patent: US2018/258076,2018,A1 .Location in patent: Paragraph 0486; 0487
[2]Patent: JP2018/199673,2018,A .Location in patent: Paragraph 0161

60
ethyl 2-(4-chloro-2-hydroxyphenyl)acetate [ No CAS ]
[ 110661-91-1 ]
tert-butyl 4-(5-chloro-2-(2-ethoxy-2-oxoethyl)phenoxy)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.7 g	With caesium carbonate; In N,N-dimethyl-formamide; at 10 - 20℃;	To a suspension of ethyl 2-(4-chloro-2-hydroxyphenyl)acetate 4b (8.5 g, 39.6 mmol) and Cs2CO3(25.8 g, 79.2 mmol) in DMF (130 mL) at 10C was added dropwise terf-butyl 4-bromobutanoate [CAS 1 1061 1 -91 -1 ] (7 mL, 39.6 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and water. The layers were decanted. The organic layer was washed with water, dried over MgSO4, filtered and the solvent was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (15-40 muiotatauiota, 120 g, heptane/EtOAc 90/10). The pure fractions were combined and concentrated to dryness to give terf-butyl 4-(5-chloro-2-(2-ethoxy-2- oxoethyl)phenoxy)butanoate 11a (12.7 g).
12.7 g	With caesium carbonate; In N,N-dimethyl-formamide; at 10 - 20℃;	To a suspension of ethyl 2-(4-chloro-2-hydroxyphenyl)acetate [CAS 1261826-30-5] (8.5 g, 39.6 mmol), C52CO3 (25.8 g, 79.2 mmol) in DMF (130 mL) at 10C was added dropwise tert-butyl 4-bromobutanoate [CAS 110611-91-1] (7 mL, 39.6 mmol). The mixture was stirred at room temperature overnight. The mixture wasdiluted with EtOAc and water. The layers were separated. The organic layer was washed with water, dried over MgSO4, filtered and the solvent was concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel (15-40 pm, 120 g, heptane/EtOAc 90/1 0). The pure fractions were combined and concentrated to dryness to give tert-butyl 4-(5-chloro-2-(2-ethoxy-2-oxoethyl)phenoxy)butanoate 7a (12.7 g).

Reference： [1]Patent: WO2018/178240,2018,A1 .Location in patent: Page/Page column 52; 53
[2]Patent: WO2018/178238,2018,A1 .Location in patent: Page/Page column 39

61
(S)-2-((1H-pyrazol-4-yl)ethynyl)-4-(4-chlorophenyl)-3,6,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine [ No CAS ]
[ 110661-91-1 ]
tert-butyl (S)-4-(4-((4-(4-chlorophenyl)-3,6,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;	To compound 1 (866 mg, 2 mmol, 1.0 eq) in 10 mL DMF was added Cs2CO3 (2.Og, 6 mmol, 3.0 eq) and tert-butyl 4-bromobutanoate the (892 mg, 4 mmol, 2.0 eq) and the mixture was stirred at 80 C for 5 h. To above solution, ethyl acetate (80 mL) was added, and washed with H20 (3X 15 mL). The organic layers were combined, dried and purified by DCM/MeOH to afford tert-butyl (S )-4-(4-((4-(4-chlorophenyl)-3 ,6,9-trimethyl-6H-thieno [3 ,2-fj [1 ,2,4j triazolo[4,3 aj [1 ,4j diazepin-2-yl)ethynyl)- 1 H-pyrazol- 1- yl)butanoate (Intermediate 2). Yield: 80 %. UPLC-MS [M+1j: 519.20.

Reference： [1]Patent: WO2019/55444,2019,A1 .Location in patent: Paragraph 0377-0378

62
2-O-[4-((3-(aminomethyl)benzyl)oxy)-3,5-dichloro-2-methylbenzoyl]-1-O-methyl-α-D-glucopyranoside hydrochloride [ No CAS ]
[ 110661-91-1 ]
C₃₁H₄₁Cl₂NO₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;	To a solution of 4-((3-(aminomethyl)benzyl)oxy)-3,5-dichloro-2-methylbenzoyl-methyl-a- D-glucopyranoside hydrochloride (100 mg, 169.70 mumol, synthesized following the procedure described in method L*15) in DMF (0.5 mL) K2CO3(70.36 mg, 509.09 mumol) and tert-butyl 4-bromobutanoate (45 mul, 254.55 mumol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by LC/MS. After 16 h at room temperature the reaction mixture was evaporated and purified by preparative HPLC (YMC-Actus Triart Prep C18-S 250x30 S-10 mum, 12 nm, 70 mL/min; 0-2 min 5 % acetonitrile in H2O + 0.05 % trifluoroacetic acid, 2-10 min 5 to 100 % acetonitrile in H2O + 0.05 % trifluoroacetic acid, 20-22 min: 100 % acetonitrile) to yield 12 mg (18.8 mumol, 11 % yield) of the desired product.

Reference： [1]Patent: WO2019/106122,2019,A1 .Location in patent: Page/Page column 92-93; 167

63
[ 1435263-65-2 ]
[ 110661-91-1 ]
tert-butyl 4-((2-oxo-2-((1-phenethylpiperidin-4-yl)(phenyl)amino)ethyl)amino)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 10h;Inert atmosphere;	To a solution of primary amine 28 (42.8 mg, 0.127 mmol) in DMF (0.3 mL) was added asolution of tert-butyl 4-bromobutanoate (28.3 mg, 0.127 mmol) in DMF (1.0 mL) and K2CO3(35.1 mg, 0.254 mmol). The reaction mixture was stirred at room temperature for 10 h. Themixture was diluted with CH2Cl2 (10 mL), washed with saturated NaHCO3 aq. (3 mL), and driedwith Na2SO4. After filtration and evaporation, the crude was purified by silica gelchromatography (CH2Cl2/MeOH 19:1 to 9:1) to give compound 29 as a colorless oil (23.6 mg,39%) and starting material (21.3 mg, 50%)

Reference： [1]Beilstein Journal of Organic Chemistry,2019,vol. 15,p. 1020 - 1031

64
1-((3-chloro-2-methylphenyl)sulfonyl)-2-(3-(3-methylpyridin-4-yl)phenyl)piperazine hydrochloride [ No CAS ]
[ 110661-91-1 ]
tert-butyl 4-(4-((3-chloro-2-methylphenyl)sulfonyl)-3-(3-(3-methylpyridin-4-yl)phenyl)piperazin-1-yl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		N,N-Diisopropylethylamine (0.24 niL, 1.40 mmol)was added to a suspension ofl- ((3-chloro-2-methylphenyl)sulfonyl)-2-(3-(3-methylpyridin-4-yl)phenyl)piperazine hydrochloride (0.26 g, 0.54 mmol) in DMF (2 mL). The mixture was stirred for 5 minutes. After tert-bu yl 4-bromobutanoate (124 uL, 0.70 mmol) was added, the reaction vessel was capped and heated to 70C for 20 hours. Additional portions of NN- diisopropylethylamine (45 uL) and tert-butyl 4-bromobutanoate (35 uL) were added, and the reaction mixture was heated to 80C for an additional 16 hours. The reaction mixture was diluted with EtOAc (40 mL), washed with water (25 mL), brine (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gelchromatography (5 - 70% EtOAc/hexanes) yielded Compound 52A (122 mg, 39%). 1H NMR (CDC13) delta 8.48 (m, 2H), 7.78 (d, 1H), 7.49 (m, 2H), 7.29 (m, 2H, overlapping with CDCI3), 7.16 (m, 2H), 7.02 (d, 1H), 4.91 (m, 1H), 3.62 (m, 1H), 3.40 (m, 1H), 3.18 (m, 1H), 2.78 (m, 1H), 2.65 (m, 1H), 2.57 (s, 3H), 2.40-2.22 (m, 5H), 2.24 (s, 3H), 1.78 (m, 2H), 1.43 (s, 9H).

Reference： [1]Patent: WO2018/5801,2018,A2 .Location in patent: Page/Page column 262; 263

65
[ 622-08-2 ]
[ 110661-91-1 ]
tert-butyl 4-(2-(benzyloxy)ethoxy)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	With sodium hydroxide; In toluene; at 20℃; for 16h;	A mixture of fert-butyl 4-bromobutanoate (22.0 g, 98.6 mmol), 2- (benzyloxy)ethanol (6.00 g, 39.4 mmol) and sodium hydroxide (3.23 g, 78.9 mmol) in toluene (75.0 mL) was stirred at room temperature for 16 hours. The resulting solution was partitioned between water and EtOAc. Phases were separated. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0%-20% ethyl acetate/petroleum ether) to yield 530 mg (5%) of the title compound as a colorless oil. LCMS (ESI): RT (min) = 1.45, [M+Na]+ = 317, method =A.

Reference： [1]Patent: WO2019/84026,2019,A1 .Location in patent: Paragraph 0899

66
[ 99-76-3 ]
[ 110661-91-1 ]
methyl 4-(4-tert-butoxy-4-oxobutoxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	General procedure: To 100 mLrbf was added a mixture of compound 20 (1.66 g, 10 mmol), cesiumcarbonate (3.26 g, 10 mmol), TBAI (3.70 g, 10 mmol) and anhydrousDMF (20 mL). Compound 19 (2.23 g, 10 mmol) was added dropwise tothe mixture. The reaction mixture was then stirred at room temperaturefor 3 h. Ethyl acetate was added into the reaction mixture. The combinedmixture was washed with two portions of water. After evaporationof the solvent under reduced pressure MeOH (20 mL) was addedfollowed by silica gel (1 g). The resulting plug was loaded on to a silicagel column and eluted with 1:10 (ethyl acetate: hexane). Fractions withand Rf = 0.64 (hexane:ethyl acetate 1:1) were pooled and evaporatedto afford tert-butyl esters (1.47 g, yield; 47%). Trifluoroacetic acid wasthen added into the tert-butyl esters and mixture was stirred at roomtemperature for 30 min. Excess of trifluoroacetic acid was evaporatedand MeOH (20 mL) was added followed by silica gel (1 g). The resultingplug was loaded on to a silica gel column and eluted with 1:10 (ethylacetate: hexane). Fractions with and Rf = 0.45 (TLC) (Hexane: ethylacetate,1:1) were pooled and evaporated to afford 22 (1 g, yield 83%)as white solid.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 5148 - 5175
[2]Bioorganic and Medicinal Chemistry,2020,vol. 28

67
[ 79370-78-8 ]
[ 110661-91-1 ]
tert-butyl 4-(3,5-dicyanophenoxy)butanoate [ No CAS ]